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1.  EULAR recommendations reflect advances in imaging 
Nature reviews. Rheumatology  2015;11(7):388-389.
Substantial advances have been made in the field of imaging in spondyloarthritis, with respect to both the techniques themselves and their applications, but how should clinicians and radiologists make the most of these developments? New recommendations from EULAR could provide valuable guidance.
doi:10.1038/nrrheum.2015.80
PMCID: PMC4493421  PMID: 26055546
2.  An update on the contribution of the MHC to as susceptibility 
Clinical rheumatology  2014;33(6):749-757.
The 40-year-old association of HLA-B27 with ankylosing spondylitis is one of the best examples of disease association with a hereditary marker. Genomewide association and family studies suggest that other important major histocompatibility complex (MHC) influences are operative in ankylosing spondylitis (AS) susceptibility. HLA-B27 positive hepatitis C individuals are immunologically more efficient in combating viral infections such as HIV-1, hepatitis C, and influenza and less efficient in combating against certain bacteria (and perhaps other organisms) capable of surviving intracellularly. A recent representative population survey of the frequency of HLA-B27 in the USA found a lower frequency of HLA-B27 in older US adults, perhaps reflecting this. Other HLA class I and class II alleles have been implicated in AS susceptibility, the most consistent being HLA-B*40/B60 (B*40:01) but also B14, B15, A*0201, DRB1*04:04, and certain DPA1 and DPB1 alleles. Non-HLA MHC alleles have also been implicated, although many such studies have been inconsistent, likely due to power issues related to the low number of HLA-B27-negative AS patients examined. The best evidence is for major histocompatibility complex class I chain-related gene A (MICA) whose recognition by intestinal epithelial T cells expressing different V-delta-1 gamma/delta TCR further implicates the gut in AS pathogenesis. The HLA class I and class II and other non-HLA allelic associations underscore the importance of T cells in AS pathogenesis.
doi:10.1007/s10067-014-2662-7
PMCID: PMC4488903  PMID: 24838411
Ankylosing spondylitis; Genetics; HLA genes; HLA-B27; Major histocompatibility complex; MIC-A; Spondylitis; Spondyloarthritis
3.  Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis 
Clinical rheumatology  2015;34(6):1009-1018.
With the growing awareness of the impact of chronic back pain and axial spondyloarthritis and recent breakthroughs in genetics and the development of novel treatments which may impact best on early disease, the need for markers that can facilitate early diagnosis and profiling those individuals at the highest risk for a bad outcome has never been greater. The genetic basis of ankylosing spondylitis has been considerably advanced, and HLA-B27 testing has a role in the diagnosis. Knowledge is still incomplete of the rest of the genetic contribution to disease susceptibility, and it is likely premature to use extensive genetic testing (other than HLA-B27) for diagnosis. Serum and plasma biomarkers have been examined extensively in assessing disease activity, treatment response, and as predictors or radiographic severity. For assessing disease activity, other than C-reactive protein and erythrocyte sedimentation rate, the most work has been in examining cytokines (particularly interleukin 17 and 23), matrix metalloproteinase (MMP) markers (particularly MMP3). For assessing those at the highest risk for radiographic progression, biomarkers of bony metabolism, cartilage and connective tissue degradation products, and adipokines have been most extensively assessed. The problem is that no individual biomarkers has been reproducibly shown to assess disease activity or predict outcome, and this area still remains an unmet need, of relevance to industry stakeholders, to regulatory bodies, to the healthcare system, to academic investigators, and finally to patients and providers.
doi:10.1007/s10067-015-2949-3
PMCID: PMC4488904  PMID: 25939520
Biomarkers; Diagnostic tools; Genetics; Radiographic outcome; Spondyloarthritis; Treatment response
4.  Epidemiology of Spondyloarthritis 
Synopsis
Spondyloarthritis (SpA) represents a group of interrelated diseases with common clinical features and a close association with HLA-B27. Figures on the incidence and prevalence of diseases vary highly dependent on methodological differences between studies, the case definition used to classify disease and on the prevalence of HLA-B27 in the population studied. When summarizing the available literature, incidence rates of SpA are mainly based on the ESSG criteria and range between 0.48 and 63/100.000 while prevalence rates vary between 0.01 and 2.5%. For ankylosing spondylitis (AS), the most widely recognized representative of the SpA group of diseases, incidence rates of 0.44-7.3/100.000 and prevalence rates of 0.007-1.7% have been described in studies that were based on the (modified) New York criteria to classify cases. The incidence of psoriatic arthritis (PsA) varied from 3.6 up to 23.1/100.000 in different studies and prevalence between <0.1% and 0.4%, using a variety of classification criteria. The incidence of ReA has been estimated between 0.6 up to 28/100.000 in studies based on different source populations and different case definitions. The newly proposed criteria for axial SpA and peripheral SpA present an attractive new approach to facilitate classification of the SpA into two main subtypes and the axial SpA criteria allow earlier detection of patents with inflammatory back pain. It should be emphasized that these criteria were developed for use in a (specialized) clinical setting and not for large epidemiological studies.
doi:10.1016/j.rdc.2012.09.003
PMCID: PMC4470267  PMID: 23083748
Spondyloarthritis; Ankylosing Spondylitis; Psoriatic arthritis; Reactive arthritis; Epidemiology; Incidence; Prevalence
5.  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
6.  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.
Objective
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).
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/art.33503
PMCID: PMC4038331  PMID: 22139851
8.  Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1 
Nature Communications  2015;6:7146.
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
Ankylosing spondylitis is a common, highly inheritable inflammatory arthritis with poorly understood biology. Here Brown, Cortes and colleagues use fine mapping of the major histocompatibility complex and identify novel associations, and identify other HLA alleles that like HLA-B27 interact with ERAP1 variants to influence disease risk.
doi:10.1038/ncomms8146
PMCID: PMC4443427  PMID: 25994336
9.  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.
Summary
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.
doi:10.1097/BOR.0b013e3283620e1d
PMCID: PMC3758684  PMID: 23656716
genetics; patient cohorts; registries; spondyloarthritis; treatment outcome
10.  FcγRIIIa SNPs and haplotypes affect human IgG binding and association with lupus nephritis in African Americans 
Objective
To investigate whether the FcγRIIIa-66R/H/L polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66R/H/L and FcγRIIIa-176F/V as well as copy number variation (CNV) confer risk for development of SLE and lupus nephritis.
Methods
FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG binding assays. FCGR3A SNP and CNV genotypes were determined by Pyrosequencing methodology in a cohort of 1728 SLE patients and 2404 healthy controls.
Results
The FcγRIIIa-66L/H/R (rs10127939) polymorphism influences ligand binding capacity in the context of the FcγRIIIa-176V (rs396991) allele. The low binding FcγRIIIa-176F allele was associated with SLE nephritis (p = 0.0609) in African Americans but not in European Americans (p > 0.10). Nephritis among African American SLE subjects was associated with FcγRIIIa low binding haplotypes containing the 66R/H/L and 176F variants (p = 0.03) and with low binding genotype combinations (p = 0.002). No association was observed in European American SLE patients. The distribution of FCGR3A CNV was not significantly different between controls and SLE patients with or without nephritis.
Conclusion
FcγRIIIa-66R/H/L influences ligand binding. The low binding haplotypes formed by 66R/H/L and 176F confer enhanced risk for lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or SLE nephritis in either African Americans or European Americans.
doi:10.1002/art.38337
PMCID: PMC4069204  PMID: 24782186
11.  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.
doi:10.1097/MAJ.0b013e3182514093
PMCID: PMC3613240  PMID: 22543541
Spondyloarthritis; Ankylosing Spondylitis; Psoriatic Arthritis; Economics; anti-TNF Treatment
12.  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.
doi:10.3389/fgene.2014.00450
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
13.  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.
doi:10.1097/MAJ.0b013e31820f8c99
PMCID: PMC3063892  PMID: 21430444
Epidemiology; ankylosing spondylitis; psoriatic arthritis; enteropathic arthritis; spondyloarthritis
14.  A Polymorphism in TLR2 Is Associated With Arterial Thrombosis in a Multiethnic Population of Patients With Systemic Lupus Erythematosus 
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/art.38520
PMCID: PMC4269184  PMID: 24578102
15.  Value of Isolated IgA anti-β2GPI Positivity in the Diagnosis of the Antiphospholipid Syndrome 
Arthritis and rheumatism  2013;65(12):3186-3193.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/art.38131
PMCID: PMC4048705  PMID: 23983008
16.  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.
doi:10.1093/hmg/ddt248
PMCID: PMC3766185  PMID: 23740937
17.  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.
doi:10.1371/journal.pone.0106939
PMCID: PMC4153724  PMID: 25184637
18.  Is Familial Lupus Different from Sporadic Lupus?: Data from LUMINA, a Multiethnic US Cohort 
Lupus  2010;19(11):1331-1336.
Purpose
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.
Method
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.
Results
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).
Conclusions
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.
doi:10.1177/0961203310375264
PMCID: PMC4078734  PMID: 20696771
familial lupus; lupus; sporadic lupus; LUMINA; multiethnic cohort
19.  Markers of intestinal inflammation in patients with ankylosing spondylitis: a pilot study 
Arthritis Research & Therapy  2012;14(6):R261.
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/ar4106
PMCID: PMC3674603  PMID: 23194008
20.  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.
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/acr.21968
PMCID: PMC3816494  PMID: 23401350
21.  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.
doi:10.1126/scitranslmed.3007097
PMCID: PMC3982386  PMID: 24353158
22.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/art.37917
PMCID: PMC3691007  PMID: 23728826
23.  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.
doi:10.1038/gene.2013.46
PMCID: PMC3855587  PMID: 24048351
24.  Prevalence of Axial Spondylarthritis in the United States: Estimates From a Cross-Sectional Survey 
Arthritis care & research  2012;64(6):905-910.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/acr.21621
PMCID: PMC4032290  PMID: 22275150
25.  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.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.3899/jrheum.110071
PMCID: PMC3149738  PMID: 21572159
Scleroderma; GENISOS; anti-U3-RNP; digital ulcer; HLA DRB1; and Scleroderma Family Registry

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