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1.  The Epidemiology of Back Pain, Axial Spondyloarthritis and HLA-B27 in the United States 
The concept of inflammatory back pain (IBP) evolved in the 1970s, coincident with the discovery of the HLA-B27 association with ankylosing spondylitis (AS), leading to the development of criteria to determine the presence of IBP. The concept of IBP and it relationship with AS and axial spondyloarthritis (AxSpA) has further evolved, and an instrument developed (the Spondylitis Association of America Back Pain Tool), which was further modified and field tested for use in the 2009-2010 National Health and Nutrition Examination Survey (NHANES). This has shown the frequency of chronic back pain to have risen to 19.4%, with nearly one-third having IBP. The prevalence of AxSpA has been defined at 1.0-1.4% and AS at 0.52-0.55%. The national prevalence of HLA-B27 in the U.S. is 6.1%, and intriguing data from NHANES 2009 suggest a decreasing frequency with increasing age. From this arise new questions and a work agenda ahead.
PMCID: PMC4122314  PMID: 23841117
Epidemiology; Spondyloarthritis; HLA-B27; Back Pain; Ankylosing Spondylitis
2.  The Prevalence of HLA–B27 in the US: Data From the US National Health and Nutrition Examination Survey, 2009 
Arthritis and rheumatism  2012;64(5):1407-1411.
To carry out the first large-scale population study of the prevalence of HLA–B27 in the US, which is needed for public health planning purposes because of recent improvements in medical therapy and diagnostic testing for ankylosing spondylitis (AS).
The national prevalence of HLA–B27 was determined as part of the 2009 US National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey monitoring the health and nutritional status of the US civilian, noninstitutionalized population. DNA polymerase chain reaction analysis was conducted in samples from 2,320 adults ages 20–69 years from this nationally representative sample.
The age-adjusted US prevalence of B27 was 6.1% (95% confidence interval [95% CI] 4.6–8.2). By race/ethnicity, the prevalence of B27 was 7.5% (95% CI 5.3–10.4) among non-Hispanic whites and 3.5% (95% CI 2.5–4.8) among all other US races/ethnicities combined. In Mexican Americans, the prevalence was 4.6% (95% CI 3.4–6.1). The prevalence of B27 could not be reliably estimated for other US racial/ethnic groups because of the low number of B27-positive individuals in those groups. For adults 50–69 years of age, the prevalence of B27 was 3.6% (95% CI 2.2–5.8), which suggested a decrease in B27 with age. These prevalence estimates took into account the NHANES survey design and are reviewed with respect to data from the medical literature.
Our findings provide the first US national prevalence estimates for HLA–B27. A decline in the prevalence of HLA–B27 with age is suggested by these data but must be confirmed by additional studies.
PMCID: PMC4038331  PMID: 22139851
3.  A registry of ankylosing spondylitis registries and prospects for global interfacing 
Current opinion in rheumatology  2013;25(4):468-476.
Purpose of review
To review the optimal criteria and conditions for establishing a clinical registry, as well as detailing their application in a number of ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA) Registries already in existence.
Recent findings
Recent genetic studies and studies of long-term treatment efficacy and side-effects have underscored the need for large numbers of patients, much larger than would be possible from a single center or consortium. An optimal Registry should have its aims established upfront, with appropriate governance and oversight, and inclusion and exclusion criteria for participating collaborators and subject defined. Collaborators contributing subjects to a Registry should use validated instruments for which they have been previously trained. The numerous cross-sectional and longitudinal Registries on AS and axSpA have been recently established that differ widely depending on the referral and selection issues.
The challenge of large-scale examinations of genetics, comorbidities, medication usage, and side-effects in spondyloarthritis underscores the need for combining data from well characterized registries of AS patients which require careful planning. There are currently many such registries available internationally, offering promise for collaborations and data pooling that can answer some of the pressing questions facing rheumatology clinicians and researchers.
PMCID: PMC3758684  PMID: 23656716
genetics; patient cohorts; registries; spondyloarthritis; treatment outcome
4.  Economic Considerations of the Treatment of Ankylosing Spondylitis 
Ankylosing spondylitis (AS)is associated with both significant direct and indirect costs,which vary by country, and have generally increased dramatically since the introduction of anti-TNF therapy. The cost-effectiveness of biologic agents is controversial, although cost-effectiveness studies need to consider the potential impact of anti-TNF treatments on work ability. Alternatives to reduce costs associated with biologics have been examined, including on-demand dosing and lower dose alternatives. Other treatment measures, such as total hip arthroplasty and physical therapy, are also effective in reducing pain and improving function in patients with AS, although the optimal type or combination of physical therapy treatment modalities, the optimal frequency and duration of treatment, and whether therapy is equally effective in stable disease and uncontrolled AS needs to be determined. No studies have examined differences in patient outcomes based on subspecialty care. Establishing an evidence base for these questions would help inform policy decisions to design the most cost-effective measures to treat AS.
PMCID: PMC3613240  PMID: 22543541
Spondyloarthritis; Ankylosing Spondylitis; Psoriatic Arthritis; Economics; anti-TNF Treatment
5.  Lupus risk variants in the PXK locus alter B-cell receptor internalization 
Frontiers in Genetics  2015;5:450.
Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3′ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10−10, OR 0.81 (0.75–0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
6.  A Polymorphism in TLR2 Is Associated With Arterial Thrombosis in a Multiethnic Population of Patients With Systemic Lupus Erythematosus 
Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis.
We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64 ancestry-informative markers (AIMs). We first analyzed association with arterial and venous thrombosis in the combined population via logistic regression, adjusting for top principal components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to meta-analysis (after stratification by ethnicity and study population) to confirm the association and to test for study population or ethnicity effects.
In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was significantly associated with arterial thrombosis (logistic P = 6.4 × 10−5, false discovery rate P = 0.0044). Two additional SNPs in TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval 1.58–3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the effect was most significant among African Americans (OR 2.42, P = 3.5 × 10−4) and European Americans (OR 3.47, P = 0.024).
TLR2 gene variation is associated with thrombosis in SLE, particularly among African Americans and European Americans. There was no evidence of association among Hispanics, and results in Asian Americans were limited due to insufficient sample size. These results may help elucidate the pathogenesis of this important clinical manifestation.
PMCID: PMC4269184  PMID: 24578102
7.  Epidemiology of Spondyloarthritis in North America 
Many challenges have made it difficult to determine the prevalence of spondyloarthritis (SpA) in North America. They include the ethnic heterogeneity of the population, the lack of feasibility of applying current criteria (such as requirements for HLA-B27 testing and imaging studies such are pelvic radiographs and MRI scanning) and the transient nature of some SpA symptoms (ie, peripheral arthritis, enthesitis). Current estimates of the prevalence of SpA in the United States range between 0.2% and 0.5% for ankylosing spondylitis, 0.1% for psoriatic arthritis, 0.065% for enteropathic peripheral arthritis, between 0.05% and 0.25% for enteropathic axial arthritis, and an overall prevalence of SpA as high as over one percent. With newer population-based instruments becoming available, the availability of the widely validated European Spondyloarthropathy Study Group (ESSG) criteria and the lower cost and greater feasibility of genetic testing, opportunities for true population-based studies of SpA are possible and will likely soon ensue.
PMCID: PMC3063892  PMID: 21430444
Epidemiology; ankylosing spondylitis; psoriatic arthritis; enteropathic arthritis; spondyloarthritis
8.  Value of Isolated IgA anti-β2GPI Positivity in the Diagnosis of the Antiphospholipid Syndrome 
Arthritis and rheumatism  2013;65(12):3186-3193.
To examine the prevalence of isolated IgA anti-β2Glycoprotein I (anti-β2GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2GPI, with clinical manifestations of the Antiphospholipid Syndrome (APS) in three patients groups. The pathogenicity of IgA anti-β2GPI was also evaluated in a mouse model of thrombosis.
Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n=558), patients with SLE from the Hopkins Lupus Cohort (n=215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n=5,098) were evaluated. IgA anti-β2GPI titers and binding to domain IV/V of β2GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti- β2GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity.
A total of 198 patients were found to be positive for IgA anti-β2GPI isotype, and 57 patients were positive exclusively for IgA anti-β2GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2GPI positive serum samples reacted with domain IV/V of anti-β2GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2GPI positivity was associated with an increased risk for arterial thrombosis (p<0.001), venous thrombosis (p=0.015) and all thrombosis (p<0.001). The association between isolated IgA anti-β2GPI and arterial thrombosis (p=0.0003) and all thrombosis (p=0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls.
Isolated IgA anti-β2GPI positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid (aPL) tests are negative and APS is suspected is recommended. IgA anti-β2GPI antibodies directed to domain IV/V of β2GPI represent an important subgroup of clinically relevant antiphospholipids.
PMCID: PMC4048705  PMID: 23983008
9.  A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci 
Human Molecular Genetics  2013;22(19):4021-4029.
Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21 109 (6835 cases and 14 274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10−11, OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10−11, OR = 1.20) and JAZF1 (P = 1.11 × 10−8, OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
PMCID: PMC3766185  PMID: 23740937
10.  Association of the HLA-DRB1 with Scleroderma in Chinese Population 
PLoS ONE  2014;9(9):e106939.
Multiple alleles of the Human leukocyte antigen (HLA) DRB1 have been strongly associated with systemic sclerosis (SSc) and its clinical or serological subsets. However, the associations vary in different ethnic populations. To define SSc-risk and/or -protective alleles of HLA-DRB1 in Chinese population, we studied a Han Chinese cohort containing 585 patients with SSc and 458 gender-matched, unrelated controls. The HLA-DRB1 genotyping was performed with sequence-based typing method. Exact p-values were obtained (Fisher’s test) from 2×2 tables of allele frequency and disease status. The major SSc-risk allele subtypes of HLA-DRB1 are the DRB1*15∶02 and *16∶02 in this Chinese cohort. Particularly, DRB1*15∶02 was most significantly associated with anti-centromere autoantibodies (ACA) positive, and DRB1*16∶02 with anti-topoisomerase I autoantibodies (ATA) positive patients. On the other hand, DRB1*01∶01 and *04∶06 were strong SSc-protective alleles in Chinese, especially in patients who were ACA positive and had diffuse cutaneous SSc (dcSSc), respectively. In addition, DRB1*11 and *07∶01 also showed significant association with SSc as a risk for and protection from SSc, respectively, and which is consistent with the studies of Spanish, US Caucasian and Hispanic populations. DRB1*15 was associated with ATA positive Chinese SSc that is consistent with Black South African and Korean SSc. These findings of HLA-DRB1 alleles in association with Chinese SSc provide the growing knowledge of genetics of SSc, and indicate that the genetic heterogeneity among ethnicities may significantly impact the complex trait of SSc.
PMCID: PMC4153724  PMID: 25184637
11.  Is Familial Lupus Different from Sporadic Lupus?: Data from LUMINA, a Multiethnic US Cohort 
Lupus  2010;19(11):1331-1336.
To characterize the clinical features of familial lupus, and determine its influence on damage accrual and survival using data from LUMINA, a longitudinal multiethnic US cohort.
Familial lupus was defined as patients with a first degree relative with SLE. Relative risks were estimated by logistic regression; odds ratios (OR) and their 95% confidence intervals (CI) were the measure of association for familial lupus. Hazard Ratios (HR) were calculated using Cox proportional hazard adjusted for potential confounders for damage and survival.
Thirty-two of 644 patients had familial and 612 had sporadic lupus; both groups were of comparable age (~ 36 years). Familial lupus patients were in decreasing order of frequency siblings, parents and children. In multivariable analyses, mucosal ulcers (OR=1.92, 95% CI 0.65–5.70), mitral valve prolapse (OR=1.74, 95% CI 0.50–6.10), cerebrovascular disease (OR=4.18, 95% CI 0.98–17.76) and oral contraceptive use (ever/never; OR=2.51, 95% CI 0.88–7.19) were more likely in familial lupus but a history of low platelet count (<150,000/mm3; OR=0.31, 95% CI 0.08–1.17) and pulmonary disease activity (OR=0.39, 95% CI 0.14–1.20) were less likely. However, none of these associations reached statistical significance. Familial lupus was not significantly associated with a shorter time to either damage accrual or death (HR=0.77, 95% CI 0.37–1.59, p = 0.4746 and HR=0.20, 95% CI 0.03–1.47, p = 0.2020, respectively).
Although some clinical differences were observed in patients with familial and sporadic lupus, familial lupus was not associated with a significantly greater disease burden (damage, survival) than sporadic lupus.
PMCID: PMC4078734  PMID: 20696771
familial lupus; lupus; sporadic lupus; LUMINA; multiethnic cohort
12.  Does C-Reactive Protein Predict the Long-Term Progression of Interstitial Lung Disease and Survival in Patients With Early Systemic Sclerosis? 
Arthritis care & research  2013;65(8):10.1002/acr.21968.
There are no identified clinical markers that reliably predict long-term progression of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma). Elevated C-reactive protein (CRP) levels have been reported in SSc patients. We examined the predictive significance of CRP level for long-term ILD progression in a large early SSc cohort.
First, the CRP levels were compared between baseline samples of 266 SSc patients enrolled in the Genetics Versus Environment in Scleroderma Outcome Study cohort and 97 unaffected matched controls. Subsequently, the correlation between CRP levels and concomitantly obtained markers of disease severity was assessed. Serially obtained % predicted forced vital capacity (FVC) was used to examine the long-term ILD progression. The predictive significance of CRP level was investigated by a joint analysis of longitudinal measurements (serial FVCs up to 13 years) and survival data. This approach allowed inclusion of all 1,016 FVC measurements and accounted for survival dependency.
We confirmed that baseline CRP levels were higher in SSc patients than controls. CRP levels were associated with absence of anticentromere antibodies and correlated with the concomitant severity of lung, skin, and joint involvement. More importantly, higher baseline CRP levels were associated with shorter survival (P < 0.001) and predicted the long-term decline in FVC independent of potential confounders (age at baseline, sex, ethnicity, disease type, current smoking, body mass index, topoisomerase status, and treatment with immunosuppressive agents) in the multivariable model (P = 0.006).
Baseline CRP levels are predictive of long-term ILD progression. CRP level might aid clinicians in identifying patients that require more intensive monitoring and treatment.
PMCID: PMC3816494  PMID: 23401350
13.  Allelic Dependent Expression of an Activating Fc receptor on B cells Enhances Humoral Immune Responses 
Science translational medicine  2013;5(216):216ra175.
B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.
PMCID: PMC3982386  PMID: 24353158
14.  Markers of intestinal inflammation in patients with ankylosing spondylitis: a pilot study 
Arthritis Research & Therapy  2012;14(6):R261.
Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) are similar chronic inflammatory diseases whose definitive etiology is unknown. Following recent clinical and genetic evidence supporting an intertwined pathogenic relationship, we conducted a pilot study to measure fecal calprotectin (fCAL) and IBD-related serologies in AS patients.
Consecutive AS patients were recruited from a long-term prospectively collected longitudinal AS cohort at Cedars-Sinai Medical Center. Controls were recruited from Cedars-Sinai Medical Center employees or spouses of patients with AS. Sera were tested by ELISA for IBD-associated serologies (antineutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibody IgG and IgA, anti-I2, anti-OmpC, and anti-CBir1). The Bath Ankylosing Spondylitis Disease Activity Index, the Bath Ankylosing Spondylitis Functional Index, and the Bath Ankylosing Spondylitis Radiology Index were completed for AS patients.
A total of 81 subjects (39 AS patients and 42 controls) were included for analysis. The average age of AS patients was 47 years and the average disease duration was 22 years. AS patients were predominantly male; 76% were HLA-B27-positive. Median fCAL levels were 42 μg/g and 17 μg/g in the AS group and controls, respectively (P < 0.001). When using the manufacturer's recommended cutoff value for positivity of 50 μg/g, stool samples of 41% of AS patients and 10% of controls were positive for fCAL (P = 0.0016). With the exception of ANCA, there were no significant differences in antibody levels between patients and controls. Median ANCA was 6.9 ELISA units in AS patients and 4.3 ELISA units in the controls. Among AS patients stratified by fCAL level, there were statistically significant differences between patients and controls for multiple IBD-associated antibodies.
Calprotectin levels were elevated in 41% of patients with AS with a cutoff value for positivity of 50 μg/g. fCAL-positive AS patients displayed higher medians of most IBD-specific antibodies when compared with healthy controls or fCAL-negative AS patients. Further studies are needed to determine whether fCAL can be used to identify and characterize a subgroup of AS patients whose disease might be driven by subclinical bowel inflammation.
PMCID: PMC3674603  PMID: 23194008
15.  Electronic Monitoring of Oral Therapies in Ethnically Diverse and Economically Disadvantaged Patients with Rheumatoid Arthritis. Consequences of Low Adherence 
Arthritis and rheumatism  2013;65(6):1421-1429.
To quantify adherence to oral therapies in ethnically diverse and economically disadvantaged patients with rheumatoid arthritis (RA) using electronic medication monitoring, and to evaluate the clinical consequences of low adherence.
107 patients with RA enrolled in a 2-year prospective cohort study agreed to have their oral RA drug therapy intake electronically monitored, with the Medication Events Monitoring System (MEMS®). Adherence to disease-modifying antirheumatic drugs (DMARDs) and prednisone were determined as the percentage of days (or weeks for methotrexate) in which the patient took the correct dose as prescribed by the physician. Patient outcomes were assessed including the Modified Health Assessment Questionnaire (MHAQ), the Disease Activity Index 28 (DAS28), quality of life and radiological damage using Sharp-van der Heijde scores.
Adherence to the treatment regimen as determined by percent of correct doses was 64% for DMARDs and 70% for prednisone. Patients who had better mental health were statistically more likely to be adherent. Only 23 (21%) of the patients had an average adherence to DMARDs ≥ 80%. These patients showed significantly better disease activity scores across 2 years of follow-up than those who were less adherent (DAS28 3.3±1.3 vs. 4.1±1.2, p<0.02). Radiological scores were also worse in non-adherent patients at baseline and 12 months.
Only one fifth of the RA patients had an overall adherence of at least 80%. Less than two thirds of the prescribed DMARD doses were correctly taken. Adherent patients had lower disease activity and radiological damage scores across the 2 years of follow-up.
PMCID: PMC3691007  PMID: 23728826
16.  Association between Copy Number Variations HLA-DQA1 and Ankylosing Spondylitis in Chinese Han population 
Genes and immunity  2013;14(8):10.1038/gene.2013.46.
Ankylosing spondylitis (AS) is a chronic inflammatory disease with complex genetic traits. Multiple sequence variations have been associated with AS, but explained only a proportion of heritability. The studies herein aimed to explore potential associations between genomic copy number variation (CNV) and AS of Han Chinese. Five AS patients were examined with the high-density comparative genomic hybridization (CGH) microarrays in the first screen test for AS associated CNVs. A total of 533 AS patients and 792 unrelated controls were examined in confirmation studies with the AccuCopy assays. A significant association was observed between the CNV of the HLA-DQA1 and AS. Comparing with controls, AS patients showed an aberrant copy number (CN), and significantly increased number of patients had more than 2 copies of the HLA-DQA1. Therefore, CNV of the HLA-DQA1 may play an important role in susceptibility to AS in Han Chinese population.
PMCID: PMC3855587  PMID: 24048351
17.  Prevalence of Axial Spondylarthritis in the United States: Estimates From a Cross-Sectional Survey 
Arthritis care & research  2012;64(6):905-910.
The US national prevalence of spondylarthritis (SpA) was estimated for 2 published sets of classification criteria: the Amor criteria and the European Spondylarthropathy Study Group (ESSG) criteria. These 2 SpA criteria sets have been the most widely utilized in previous population-based studies of SpA.
The US SpA prevalence estimates were based on a representative sample of 5,013 US adults ages 20 – 69 years who were examined in the US National Health and Nutrition Examination Survey (NHANES) 2009–2010.
The overall age-adjusted prevalence of definite and probable SpA by the Amor criteria was 0.9% (95% confidence interval [95% CI] 0.7–1.1%), corresponding to an estimated 1.7 million persons (95% CI 1.4–2.1 million persons). The age-adjusted prevalence of SpA by the ESSG criteria was 1.4% (95% CI 1.0–1.9%), corresponding to an estimated 2.7 million persons (95% CI 1.9–3.7 million persons). There were no statistically significant sex differences in SpA prevalence. The SpA prevalence among non-Hispanic white persons was 1.0% (95% CI 0.7–1.5%) by the Amor criteria and 1.5% (95% CI 1.0–2.3%) by the ESSG criteria. SpA prevalence could not be reliably estimated in other race/ethnicity subgroups due to sample size imitations.
The SpA prevalence estimates are in the range of SpA prevalence estimates reported elsewhere in population-based surveys and it is likely that SpA may affect up to 1% of US adults, a prevalence similar to that reported for rheumatoid arthritis. The current US SpA prevalence estimates may be lower than the true value because the NHANES 2009–2010 data collection did not capture a complete set of the elements specified in the 2 SpA criteria sets.
PMCID: PMC4032290  PMID: 22275150
18.  End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1 
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
PMCID: PMC4002759  PMID: 24504811
19.  Anti-Fibrillarin Antibody in African American Patients with Systemic Sclerosis: Immunogenetics, Clinical Features, and Survival Analysis 
The Journal of rheumatology  2011;38(8):1622-1630.
Anti-U3-RNP or anti-fibrillarin antibodies (AFA) are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. The current study examines the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
Overall, 278 AA SSc patients and 328 unaffected AA controls were enrolled from three North American cohorts. Clinical features, autoantibody profile, and HLA-class-II genotyping were captured. To compare the clinical manifestations, relevant clinical features were adjusted for disease duration. The Cox proportional hazards regression was used to determine the effect of AFA on survival.
Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR=11.5, p<0.0001) and AFA negative SSc patients (OR=5.2, p=0.0002). AFA positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger Perivascular and lower Lung Severity Indices (p=0.004, p=0.014, p=0.019, p=0.092, p=0.006, and p=0.016, respectively). After adjustment for age at enrollment, AFA positive patients did not have different survival compared with patients without AFA (p=0.493).
These findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. Moreover, AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis, and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. However, presence of AFA did not change survival.
PMCID: PMC3149738  PMID: 21572159
Scleroderma; GENISOS; anti-U3-RNP; digital ulcer; HLA DRB1; and Scleroderma Family Registry
20.  The Impact of TNF-inhibitors on radiographic progression in Ankylosing Spondylitis 
Arthritis and rheumatism  2013;65(10):2645-2654.
We studied the effect of Tumor Necrosis Factor-Alpha (TNF)-inhibitors on progressive spine damage in Ankylosing Spondylitis (AS) patients.
All AS patients (satisfying the modified New York criteria) prospectively followed and with at least two sets of spinal radiographs at a minimum gap of 1.5 years were included (n=334). Patients received clinical standard of care, which included non-steroidal anti-inflammatory drugs and TNF-inhibitors. Radiographic severity was assessed by the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of progression more than 1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching (PSM) and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNF-inhibitor on change in mSASSS with varying follow-up periods. Potential confounders like Bath AS Disease Activity Index (BASDAI), ESR, CRP, HLA-B27, gender, age of onset, smoking and baseline damage were included in the model.
TNF-inhibitor treatment was associated with a 50% reduction in the odds of progression (OR: 0.52; CI: 0.30-0.88; p=0.02). Patients with a delay in starting therapy of more than 10 years were more likely to progress compared to those who started earlier (OR=2.4; 95% CI: 1.09-5.3; p=0.03). In the ZINB model TNF-inhibitor use significantly reduced progression when the gap between x-rays was more than 3.9 years. The protective effect of TNF-inhibitors was stronger after propensity score matching.
TNF-inhibitors appear to reduce radiographic progression in AS, especially with early initiation and longer duration of follow up.
PMCID: PMC3974160  PMID: 23818109
Arthritis care & research  2013;65(4):607-614.
Functional limitations in ankylosing spondylitis (AS) may be due to peripheral joint or axial involvement. To determine if the Bath AS Functional Index (BASFI), an axial-focused measure, can detect limitations related to peripheral joint involvement equally well as the Health Assessment Questionnaire modified for the Spondyloarthropathies (HAQ-S), a peripheral arthritis-focused measure, and vice versa, we compared associations of each questionnaire with spinal and hip range of motion, peripheral arthritis, and enthesitis in patients with AS.
We examined patients every 4 to 6 months in this prospective longitudinal study. We used mixed linear models to examine associations between ten physical examination measures and the BASFI and HAQ-S.
We studied 411 patients for a median of 1.5 years (3 visits). In multivariate analyses, cervical rotation, chest expansion, lateral thoracolumbar flexion, hip motion, tender joint count, and tender enthesis count were equally strongly associated with the BASFI and HAQ-S. Peripheral joint swelling was more strongly associated with the HAQ-S. Individual items of the BASFI were more likely than items of the HAQ-S to be associated with unrelated physical exam measures (e.g. association between difficulty rising from a chair and cervical rotation), which may have diminished the axial/peripheral distinction for the BASFI.
The BASFI and HAQ-S had similar associations with impairments in axial measures, while the HAQ-S had stronger associations with the number of swollen peripheral joints. The HAQ-S should be considered for use in studies focused on spondyloarthritis with peripheral joint involvement.
PMCID: PMC3567248  PMID: 23097327
Ankylosing spondylitis; functional limitations; metrology
22.  Predictors of the Rate of Change in Disease Activity over Time in LUMINA, a Multiethnic US Cohort of Patients with Systemic Lupus Erythematosus: LUMINA LXX 
Lupus  2010;19(6):727-733.
The objectives of the present study were (1) to clarify and quantify the relationship between age and disease duration with the rate of change in disease activity over time in patients with systemic lupus erythematosus (SLE) and (2) to explore other possible factors associated with this rate of change. To this end, SLE patients from LUMINA were studied if they had ≥3 visits in which disease activity (Systemic Lupus Activity Measure-Revised or SLAM-R) had been ascertained. Variables associated with the rate (slope) of change in disease activity (obtained by regressing the SLAM-R scores against the length of time from diagnosis to last visit) were examined by univariable and multivariable analyses. Five-hundred forty-two of the 632 patients had ≥3 SLAM-R scores. In multivariable analyses Caucasians exhibited the fastest decline in disease activity; Texan Hispanics exhibited the slowest, trailed by the African Americans. Longer disease duration and HLA-DRB1*1503 positivity were associated with a slower decline whereas a greater number of ACR criteria and abnormal laboratory parameters (white blood cell and platelet counts, hematocrit and serum creatinine) were associated with a faster decline. These findings complement existing knowledge on SLE disease activity and are potentially useful to clinicians managing these patients.
PMCID: PMC3964002  PMID: 20118158
Lupus; disease activity; rate of change; ethnicity; cohort
23.  The prevalence of inflammatory back pain: population-based estimates from the US National Health and Nutrition Examination Survey, 2009–10 
Annals of the rheumatic diseases  2012;72(3):369-373.
To estimate the current US inflammatory back pain (IBP) prevalence using four published case definitions.
Analysis of an IBP data collection instrument specifically designed for the 2009–10 National Health and Nutrition Examination Survey. Subjects were 5103 US adults ages 20–69 with complete data. IBP prevalence as determined by Calin et al criteria, European Spondylarthropathy Study Group (ESSG) criteria, and Berlin criteria 8a and 7b.
Age-adjusted US prevalence of IBP by Calin criteria was 5.0% (95% CI 4.2% to 5.8%). Prevalence of IBP was 5.6% (95% CI 4.7% to 6.5%) by ESSG criteria, and 5.8% (95% CI 5.2% to 6.4%) and 6.0% (95% CI 4.9% to 7.1%) by Berlin Criteria 8a and 7b, respectively. IBP prevalence did not differ significantly by age groups or between men and women. IBP prevalence was significantly lower among non-Hispanic black persons compared with non-Hispanic white persons for the Calin and ESSG IBP criteria. For the ESSG and Berlin 7b criteria, non-Hispanic white persons had significantly higher IBP prevalences compared with Mexican Americans.
IBP is associated with spondyloarthritis. Awareness of the prevalence of IBP may be useful for planning future epidemiological studies as well as development and validation of diagnostic and classification criteria for specific clinically defined diseases.
PMCID: PMC3954785  PMID: 22791746
Arthritis care & research  2013;65(2):257-265.
Radiographic damage and functional limitations both increase with the duration of ankylosing spondylitis (AS). We examined whether radiographic damage contributed more to functional limitations in late AS than in early AS, and if the strength of association varied with the anatomic region of damage.
In this cross-sectional study of 801 patients with AS, we examined associations of the lumbar modified Stoke AS Spine Score (mSASSS), cervical mSASSS, lumbar posterior fusion, cervical posterior fusion, and hip arthritis with the Bath AS Functional Index (BASFI) and the Health Assessment Questionnaire (HAQ-S).
Higher lumbar and cervical mSASSS were associated with more functional limitations, but there was an interaction between mSASSS and the duration of AS such that the strength of their association with functional limitations decreased with increasing duration of AS. Cervical posterior fusion was associated with worse functioning independent of mSASSS. Hip arthritis was significantly associated with functional limitations independent of measures of spinal damage. Among patients with AS ≥ 40 years, the number of comorbid conditions accounted for most of the variation in functioning. Results were similar for both the BASFI and HAQ-S.
Although both radiographic damage and functional limitations increase over time in AS, the relative contribution of radiographic damage to functional limitations is lower among patients with longstanding AS than early AS, suggesting patients may accommodate to limited flexibility. Damage in different skeletal regions impacts functioning over the duration of AS. Functional limitations due to comorbidity supervene in late AS.
PMCID: PMC3541454  PMID: 23042639
Ankylosing spondylitis; radiographic damage; functional limitations
25.  Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci 
Nature genetics  2010;42(2):123-127.
To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.
PMCID: PMC3224997  PMID: 20062062

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