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1.  The Impact of TNF-inhibitors on radiographic progression in Ankylosing Spondylitis 
Arthritis and rheumatism  2013;65(10):2645-2654.
Introduction
We studied the effect of Tumor Necrosis Factor-Alpha (TNF)-inhibitors on progressive spine damage in Ankylosing Spondylitis (AS) patients.
Methods
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.
Results
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.
Conclusions
TNF-inhibitors appear to reduce radiographic progression in AS, especially with early initiation and longer duration of follow up.
doi:10.1002/art.38070
PMCID: PMC3974160  PMID: 23818109
2.  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.
doi:10.1177/0961203309359289
PMCID: PMC3964002  PMID: 20118158
Lupus; disease activity; rate of change; ethnicity; cohort
3.  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.
Objective
To estimate the current US inflammatory back pain (IBP) prevalence using four published case definitions.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/annrheumdis-2012-201403
PMCID: PMC3954785  PMID: 22791746
4.  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
5.  REGIONAL RADIOGRAPHIC DAMAGE AND FUNCTIONAL LIMITATIONS IN PATIENTS WITH ANKYLOSING SPONDYLITIS: DIFFERENCES IN EARLY AND LATE DISEASE 
Arthritis care & research  2013;65(2):257-265.
Objective
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1002/acr.21821
PMCID: PMC3541454  PMID: 23042639
Ankylosing spondylitis; radiographic damage; functional limitations
6.  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
7.  SNPs in VKORC1 are Risk Factors for Systemic Lupus Erythematosus in Asians 
Arthritis and rheumatism  2013;65(1):211-215.
OBJECTIVE
The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. In a case-control analysis, we investigated whether 33 established and novel single nucleotide polymorphisms (SNP) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis in the general population were risk factors for SLE development among Asians.
METHODS
Patients in the discovery cohort were enrolled in one of two North American SLE cohorts. Patients in the replication cohort were enrolled in one of four Asian or two North American cohorts. SLE cases met American College of Rheumatology classification criteria. We first genotyped 263 Asian SLE and 357 healthy Asian control individuals for 33 SNPs using Luminex multiplex technology in the discovery phase, and then used Taqman and Immunochip assays to examine 5 SNPs in up to an additional 1496 cases and 993 controls in the Replication phase. SLE patients were compared to healthy controls for association with minor alleles in allelic models. Principal components analysis was used to control for intra-Asian ancestry in an analysis of the replication cohort.
RESULTS
Two genetic variants in the gene VKORC1, rs9934438 and rs9923231, were highly significant in both the discovery and replication cohorts: OR(disc) = 2.45 (p=2×10−9), OR(rep) = 1.53 (p=5×10−6) and OR(disc) = 2.40 (p=6×10−9), OR(rep) = 1.53 (p=5×10−6), respectively. These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: rs9934438 OR(adj) = 1.34 (p=0.0029) and rs9923231 OR(adj) = 1.34 (p=0.0032).
CONCLUSION
Genetic variants in VKORC1, involved in vitamin K reduction and associated with DVT, are associated with SLE development in Asians. These results suggest intersecting genetic pathways for the development of SLE and thrombosis.
doi:10.1002/art.37751
PMCID: PMC3670944  PMID: 23124848
systemic lupus erythematosus; single nucleotide polymorphisms; genetic risk factors
8.  Interferon Inducible Chemokines Correlate with Disease Severity in Systemic Sclerosis 
Arthritis and rheumatism  2013;65(1):226-235.
Objective
To measure interferon (IFN) inducible chemokines in plasma of patients with systemic sclerosis (SSc) and investigate their correlation with disease severity.
Methods
We examined the correlation of IFN-inducible chemokines, IFNγ-inducible protein-10 (IP-10/CXCL10), IFN-inducible T cell alpha chemoattractant (I-TAC/CXCL11), and monocyte chemoattractant protein-1 (MCP-1/CCL2) with the IFN gene expression signature. We generated an IFN-inducible chemokine score with the correlated chemokines, IP-10 and I-TAC and compared it in 266 SSc patients enrolled in the GENISOS cohort to that of 97 matched controls. Subsequently, the correlation between the baseline IFN-inducible chemokine score and markers of disease severity was assessed. Finally, the course of IFN-inducible chemokine score over time was examined.
Results
The plasma IFN-inducible chemokine score correlated with the IFN gene expression signature and this score was higher in SSc patients. It also was associated with the absence of anti–RNA polymerase III antibodies, presence of anti–U1 ribonucleoprotein antibodies (RNP), but not with disease duration, type, or other autoantibodies. The chemokine scores correlated with concomitantly obtained muscle, skin and lung components of the Medsger Severity Index, as well as, FVC, DLco, creatine kinase. Its association with disease severity was independent of anti-RNP or other potential confounders (age, gender, ethnicity, disease duration, and treatment with immunosuppressive agents). Finally, there was not a significant change in the IFN-inducible chemokine score over time.
Conclusions
The IFN-inducible chemokine score is a stable serological marker of more severe subtype of SSc and may be useful for risk stratification regardless of disease type or duration.
doi:10.1002/art.37742
PMCID: PMC3687352  PMID: 23055137
10.  Time to Neuropsychiatric Damage Occurrence in LUMINA: A Multiethnic Lupus Cohort 
Lupus  2009;18(9):822-830.
The aims of this study were to examine the predictors of time-to-neuropsychiatric (NP) damage and its impact on mortality in 632 systemic lupus erythematosus (SLE) African American, Hispanic and Caucasian LUMINA patients, age ≥ 16 years and disease duration ≤ 5 years at baseline (T0). Time-to-NP damage and its impact on mortality were examined by Cox proportional hazards regressions. One-hundred eighty-five (29.3%) patients developed NP-damage over a mean (SD) disease duration of 5.6 (3.7) years. After adjusting for neuropsychiatric manifestations present, older age [Hazard ratio (HR)=1.02; 95% [Confidence interval (CI) 1.00–1.04)], Caucasian ethnicity (HR=1.87; 95% CI 1.22-2.87), disease activity over the disease course (HR=1.16; 95% CI 1.12–1.21), diabetes (HR=3.47; 95% CI 1.44–8.38) and abnormal illness-related behaviors (HR=1.05; 95% CI 1.02–1.08) were associated with a shorter time to NP-damage. Photosensitivity (HR=0.65; 95% CI 0.44–0.95), anemia (HR=0.56; 95% CI 0.31–0.98), Raynaud’s phenomenon (HR=0.49; 95% CI 0.34–0.72), a medium dose of prednisone (HR=0.56; 95% CI 0.35–0.92) and hydroxychloroquine use (HR=0.58; 95% CI 0.36–0.93) were associated with a longer time. NP-damage did not contribute to mortality. Older age, Caucasian ethnicity, disease activity and abnormal illness-related behaviors are associated with a shorter time-to-NP damage; hydroxychloroquine and a medium dose of prednisone with a longer time.
doi:10.1177/0961203309104392
PMCID: PMC3759150  PMID: 19578107
11.  Peripheral Vascular Damage in Systemic Lupus Erythematosus: Data from LUMINA, a Large Multiethnic Cohort 
Lupus  2009;18(14):1303-1308.
Summary
To determine the factors associated with peripheral vascular damage in systemic lupus erythematosus (SLE) patients and its impact on survival from LUMINA, a longitudinal multiethnic cohort. Peripheral vascular damage was defined by the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI). Factors associated with peripheral vascular damage were examined by univariable and multivariable logistic regression models and its impact on survival by a Cox multivariable regression. Thirty-four (5.3%) of 637 patients (90% women, mean [SD] age 36.5 [12.6] (16-87) years developed peripheral vascular damage. Age and the SDI (without peripheral vascular damage) were statistically significant (odds ratio [OR] =1.05, 95% confidence interval [CI] 1.01-1.08; p=0.0107 and OR=1.30, 95% CI 0.09-1.56; p=0.0043, respectively) in multivariable analyses. Azathioprine, warfarin and statins were also statistically significant, glucocorticoid use was borderline statistically significant (OR=1.03, 95% CI 0.10-1.06; p=0.0975). In the survival analysis, peripheral vascular damage was independenly associated with a diminished survival (Hazard Ratio =2.36; 95% CI 1.07-5.19; p=0.0334). In short, age was independently associated with peripheral vascular damage, but so was the presence of damage in others organs (ocular, neuropsychiatric, renal, cardiovascular, pulmonary, musculoskeletal and integument) and some medications (probably reflecting more severe disease). Peripheral vascular damage also negatively affected survival.
doi:10.1177/0961203309105877
PMCID: PMC3758688  PMID: 19850658
12.  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
13.  Variable association of reactive intermediate genes with systemic lupus erythematosus (SLE) in populations with different African ancestry 
The Journal of rheumatology  2013;40(6):842-849.
Objective
Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate related genes biological candidates for disease susceptibility. This study analyzed variation in reactive intermediate genes for association with SLE in two populations with African ancestry.
Methods
A total of 244 SNPs from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls) and. Single-marker, haplotype, and two-locus interaction tests were computed for these populations.
Results
The glutathione reductase gene GSR (rs2253409, P=0.0014, OR [95% CI]=1.26 [1.09–1.44]) was the most significant single-SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575, P=0.0065, OR [95%CI]=2.10 [1.23–3.59]) and nitric oxide synthase gene NOS1 (rs561712, P=0.0072, OR [95%CI]=0.62 [0.44–0.88]) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409, P=0.00072, OR [95%CI]=1.26 [1.10–1.44]). Haplotype and two-locus interaction analyses also uncovered different loci in each population.
Conclusion
These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
doi:10.3899/jrheum.120989
PMCID: PMC3735344  PMID: 23637325
systemic lupus erythematosus; African Americans; genetic association studies; oxygen compounds; single nucleotide polymorphism
14.  FUNCTIONAL LIMITATIONS DUE TO AXIAL AND PERIPHERAL JOINT IMPAIRMENTS IN PATIENTS WITH ANKYLOSING SPONDYLITIS: ARE FOCUSED MEASURES MORE INFORMATIVE? 
Arthritis care & research  2013;65(4):607-614.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/acr.21878
PMCID: PMC3567248  PMID: 23097327
Ankylosing spondylitis; functional limitations; metrology
15.  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
16.  IRF5 polymorphism predicts prognosis in patients with systemic sclerosis 
Annals of the Rheumatic Diseases  2012;71(7):1197-1202.
Objective
The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc.
Methods
The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 – discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 – replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study.
Results
Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%.
Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant.
Conclusion
An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.
doi:10.1136/annrheumdis-2011-200901
PMCID: PMC3375372  PMID: 22440820
17.  Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis? 
Arthritis care & research  2012;64(5):780-784.
Objective
Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants.
Methods
Overall, 502 AS patients were examined, consisting of 312 who had first-degree relatives (FDR) with AS (familial) and 190 who had no FDR with AS or spondyloarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York Criteria for AS. The patients were recruited from two U.S. cohorts (NASC and PSOAS) and from the United Kingdom- Oxford cohort. The frequencies of AS susceptibility loci in IL23R, IL1R2, ANTRX2, ERAP1, two intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag SNP rs4349859 were compared between familial and sporadic cases. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size.
Results
HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (p=0.0001, OR: 4.44, CI: (2.06–9.55)). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend towards higher frequency in the multiplex cases (p=0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined.
Conclusions
HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-MHC susceptibility loci is not markedly different between the sporadic and familial cases of AS.
doi:10.1002/acr.21601
PMCID: PMC3335985  PMID: 22231927
18.  Association of Discoid Lupus with Clinical Manifestations and Damage Accrual in PROFILE: A Multiethnic Lupus Cohort 
Arthritis care & research  2012;64(5):704-712.
Objective
To determine the clinical manifestations and disease damage associated with discoid rash in a large multiethnic systemic lupus erythematosus (SLE) cohort.
Methods
SLE patients (per ACR criteria), age ≥ 16 years, disease duration ≤ 10 years at enrollment, and defined ethnicity (African American, Hispanic or Caucasian), from a longitudinal cohort were studied. Socioeconomic-demographic features, clinical manifestations and disease damage [as per the Systemic Lupus International Collaborating Clinics Damage Index (SDI)] were determined. The association of DLE with clinical manifestations and disease damage was examined using multivariable logistic regression.
Results
A total of 2,228 SLE patients were studied. The mean (standard deviation, SD) age at diagnosis was 34.3 (12.8) years and the mean (SD) disease duration was 7.9 (6.0) years; 91.8% were women. Discoid lupus was observed in 393 (17.6%) of patients with SLE. In the multivariable analysis, patients with discoid lupus were more likely to be smokers and of African-American ethnicity, and to have malar rash, photosensitivity, oral ulcers, leukopenia and vasculitis. DLE patients were less likely to be of Hispanic (from Texas) ethnicity, and to have arthritis, end-stage renal disease (ESRD), and antinuclear, anti-dsDNA and anti-phospholipid antibodies. Patients with DLE had more damage accrual, particularly chronic seizures, scarring alopecia, scarring of the skin, and skin ulcers.
Conclusion
In this cohort of SLE patients, discoid lupus was associated with several clinical features including serious manifestations such as vasculitis and chronic seizures.
doi:10.1002/acr.21581
PMCID: PMC3559016  PMID: 22190480
discoid rash; systemic lupus erythematosus; disease damage
19.  Profiling of HLA-B Alleles for Association Studies with Ankylosing Spondylitis in the Chinese Population 
Human leucocyte antigen (HLA) B*27 is a susceptibility allele to ankylosing spondylitis (AS). However, major AS-associated subtypes of HLA-B*27 and other HLA-B alleles vary in different ethnic populations. Herein, we examined HLA-B alleles in a total of 360 AS patients and 350 controls of Chinese Han ancestry. The HLA-B genotyping was performed with sequence-based typing (SBT) method. Six HLA-B*27 subtypes B*27:04, B*27:05, B*27:07, B*27:08, B*27:10 and B*27:15 were observed in the cohorts. HLA-B*27:04:01 and -B*27:05:02 appeared significantly increased in AS patients, which indicated as two major susceptibility alleles to AS. Homozygous B*27 was observed only in AS patients. There are 30 HLA-B alleles identified in the studies. HLA-B*15, especially B*15:01:01:01, appeared as the major allele type in the Chinese controls. Some common HLA-B alleles such as HLA-B*15, B*13, B*46 and B*51 were significantly reduced in Chinese AS patients. In conclusion, the studies profiled the HLA-B alleles, and identified major susceptibility subtypes of B27 to AS in Han Chinese population
doi:10.2174/1874312920130628001
PMCID: PMC3778539  PMID: 24062861
Ankylosing spondylitis (AS); HLA-B27; Chinese Han.
20.  Novel multiplex technology for diagnostic characterization of rheumatoid arthritis 
Arthritis Research & Therapy  2011;13(3):R102.
Introduction
The aim of this study was to develop a clinical-grade, automated, multiplex system for the differential diagnosis and molecular stratification of rheumatoid arthritis (RA).
Methods
We profiled autoantibodies, cytokines, and bone-turnover products in sera from 120 patients with a diagnosis of RA of < 6 months' duration, as well as in sera from 27 patients with ankylosing spondylitis, 28 patients with psoriatic arthritis, and 25 healthy individuals. We used a commercial bead assay to measure cytokine levels and developed an array assay based on novel multiplex technology (Immunological Multi-Parameter Chip Technology) to evaluate autoantibody reactivities and bone-turnover markers. Data were analyzed by Significance Analysis of Microarrays and hierarchical clustering software.
Results
We developed a highly reproducible, automated, multiplex biomarker assay that can reliably distinguish between RA patients and healthy individuals or patients with other inflammatory arthritides. Identification of distinct biomarker signatures enabled molecular stratification of early-stage RA into clinically relevant subtypes. In this initial study, multiplex measurement of a subset of the differentiating biomarkers provided high sensitivity and specificity in the diagnostic discrimination of RA: Use of 3 biomarkers yielded a sensitivity of 84.2% and a specificity of 93.8%, and use of 4 biomarkers a sensitivity of 59.2% and a specificity of 96.3%.
Conclusions
The multiplex biomarker assay described herein has the potential to diagnose RA with greater sensitivity and specificity than do current clinical tests. Its ability to stratify RA patients in an automated and reproducible manner paves the way for the development of assays that can guide RA therapy.
doi:10.1186/ar3383
PMCID: PMC3218917  PMID: 21702928
21.  The contribution of disease activity on functional limitations over time through psychological mediators: a 12-month longitudinal study in patients with ankylosing spondylitis 
Rheumatology (Oxford, England)  2011;50(11):2087-2092.
Objectives. To explore whether helplessness, internality and depression would mediate the relationship between disease activity and functional limitations in patients with AS in a 12-month longitudinal study.
Methods. A total of 294 participants with AS meeting modified New York criteria completed clinical and psychological assessments at 6-month intervals. Psychological measures evaluated helplessness, depression and internality. Path analysis evaluated the direct and indirect effects of baseline disease activity on 12-month functional limitations via the psychological measures of helplessness, internality and depression at 6 months.
Results. Baseline disease activity demonstrated direct and indirect effects on 12-month functional limitations. Helplessness and depression, but not internality, served as mediators of the relationship between disease activity and functional limitations.
Conclusion. Higher baseline disease activity predicted greater functional limitations at 12 months through helplessness and depression. Our findings suggest that helplessness and depression may constitute future treatment targets in reducing functional limitations in patients with AS.
doi:10.1093/rheumatology/ker274
PMCID: PMC3198906  PMID: 21875876
Ankylosing spondylitis; Disease activity; Functional limitations; Depression; Internality; Helplessness
22.  Entheses and Bones in Spondyloarthritis: 2008 Annual Research and Education Meeting of the Spondyloarthritis Research and Therapy Network (SPARTAN) 
The Journal of rheumatology  2009;36(7):1527-1531.
Summary
The Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), held its sixth Annual Research and Education Meeting in July 2008 in Cleveland, Ohio. The overall theme of the meeting was entheses and bones in SpA, which included presentations on the anatomy and physiology of the synovial-entheseal complex; bone formation and destruction, and the impact of inflammation on bone; the Th17 axis, HLA-B27, IL23R, and ARTS1; and breakout sessions on epidemiology and registries.
doi:10.3899/jrheum.090122
PMCID: PMC3466478  PMID: 19567633
ankylosing spondylitis; epidemiology; spondyloarthritis; spondyloarthropathies
23.  Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(10):1752-1757.
Objective
Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus.
Materials and methods
4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria.
Results
Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0×10−6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing.
Conclusion
Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.
doi:10.1136/ard.2011.154104
PMCID: PMC3232181  PMID: 21719445
24.  Determinants of Work Disability in Patients with Systemic Sclerosis: A Longitudinal Study of the GENISOS Cohort 
Objectives
To determine the prevalence, correlates, and predictors of work disability (WD) in the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS). We hypothesized that WD in systemic sclerosis (SSc) is a function of demographic, clinical, and psychosocial factors.
Methods
Patients enrolled in the GENISOS cohort were subdivided in 3 groups: work disabled, working, and retired or homemakers. The latter group (n=29) was excluded from further analysis. We used logistic regression analysis with a forward hierarchical variable selection strategy to investigate the independent correlates of WD at enrollment. Cox regression proportional Hazard’s model with a similar variable selection strategy was utilized to determine the predictors of WD in those working at enrollment.
Results
Overall, 284 patients with mean age of 48.7 years and disease duration of 2.5 (±1.6) years were enrolled into the GENISOS cohort, consisting of 83.5% female, 46.8% Caucasian, 28.9% Hispanic, and 20.4% African American. Patients were longitudinally followed for 3.9 (±3.6) years in 1438 study visits. At enrollment, 124 patients (43.7%) were work disabled whereas 131 (46.1%) were working. Lower education (p<0.001), higher Medsger Lung Severity Index (p=0.012), higher Fatigue Severity Score (FSS) (p=0.008), and less social support (p<0.001) correlated independently with WD. Of those working at baseline, 35 (26.7%) eventually developed WD. Non-Caucasian ethnicity (p=0.038), lower DLCO %predicted value (p=0.038), and higher FSS (p=0.009) at enrollment independently predicted WD on follow-up visits.
Conclusion
Demographic, clinical, and psychosocial factors correlate with WD cross-sectionally and predict WD longitudinally in the patients with SSc.
doi:10.1016/j.semarthrit.2011.01.002
PMCID: PMC3153604  PMID: 21429562
Work disability; Systemic Sclerosis; Medsger Lung Severity Index; ISEL; SF-36; Fatigue
25.  Are there gender differences in severity of ankylosing spondylitis? Results from the PSOAS cohort 
Annals of the Rheumatic Diseases  2006;66(5):633-638.
Objective
To examine the clinical and radiographic features in men and women in the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, a large well‐defined cross‐sectional study of patients with AS, in order to understand the influence of gender in determining the severity of ankylosing spondylitis.
Methods
Extensive clinical assessments and spine radiographs were performed in 302 men and 100 women with AS of ⩾20 years duration. Radiographs were scored using the Bath Ankylosing Spondylitis Radiographic Index Spine (BASRI‐spine) score (range 2–12). Functional impairment was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ‐S).
Results
Radiographic severity was worse among men. The unadjusted median BASRI‐spine score for men was 10, compared with 6.5 for women (p<0.001). Functional disability, as measured by the BASFI and HAQ‐S, was not different between men and women. However, after adjusting for radiographic spinal damage, women were found to report worse functioning than men at any given level of radiographic damage. Women had a slightly earlier age of disease onset; however, disease duration was identical in both groups. Women more frequently reported family histories of AS in first‐degree relatives and were more likely to be treated with intra‐articular steroids, sulphasalazine and prednisone.
Conclusions
Among patients with longstanding AS, men have more severe radiographic changes; findings of treatment differences suggest that women may have more peripheral arthritis. At any given level of radiographic damage, self‐reported functional limitations were worse for women.
doi:10.1136/ard.2006.060293
PMCID: PMC1954622  PMID: 17127685

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