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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.  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
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.  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
5.  Porphyromonas gingivalis and Disease-Related Autoantibodies in Individuals at Increased Risk of Rheumatoid Arthritis 
Arthritis and rheumatism  2012;64(11):10.1002/art.34595.
Purpose
To examine the relationship of Porphyromonas gingivalis (Pg) with the presence of autoantibodies in individuals at risk for rheumatoid arthritis (RA).
Methods
Participants included: 1) a cohort enriched with HLA-DR4 and 2) those at risk for RA by virtue of having a first-degree relative with RA. None satisfied 1987 ACR RA classification criteria. Autoantibodies measured included anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF; nephelometry, IgA, IgM, IgG). Individuals were considered autoantibody positive (n = 113) with ≥ 1 positive autoantibody with individuals further categorized as `high-risk' (n = 38; positive ACPA or ≥ 2 RF assays). Autoantibody negative individuals served as comparators (n = 171). Antibody to Pg, P. intermedia (Pi), and F. nucleatum (Fn) were measured. Associations of bacterial antibodies with group status were examined using logistic regression.
Results
Anti-Pg concentrations were higher in high-risk (p = 0.011) and autoantibody positive group (p = 0.010) than in the autoantibody negative group. There were no group differences in anti-Pi or anti-Fn concentrations. After multivariable adjustment, anti-Pg concentrations (but not anti-Pi or anti-Fn) were significantly associated with autoantibody positive and high-risk status (p < 0.05).
Conclusion
Immunity to Pg, but not Pi or Fn, is significantly associated with the presence of RA-related autoantibodies in individuals at risk for RA. These results support the hypothesis that infection with Pg may play a central role in the early loss of tolerance to self-antigens in RA pathogenesis.
doi:10.1002/art.34595
PMCID: PMC3467347  PMID: 22736291
rheumatoid arthritis; periodontitis; Porphyromonas gingivalis; Prevotella intermedia; Fusobacterium nucleatum; rheumatoid factor; anti-citrullinated protein antibody
6.  Elevated serum anti-flagellin antibodies implicate subclinical bowel inflammation in ankylosing spondylitis: an observational study 
Arthritis Research & Therapy  2013;15(5):R166.
Introduction
Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) share genetic and clinical features. IBD is associated with the presence of antibodies to a variety of commensal microorganisms including anti-Saccharomyces cerevesiae antibodies (ASCA), antineutrophil cytoplasmic antibodies (ANCA), anti-I2 (associated with anti-Pseudomonas activity), anti-Eschericia coli outer membrane porin C (anti-OmpC) and anti-flagellin antibodies (anti-CBir1). Subclinical intestinal inflammation may be present in up to 65% of patients with AS. This study evaluated the presence of antimicrobial antibodies in patients with AS alone, patients with AS and concomitant IBD (AS-IBD) and a control group of patients with mechanical back pain (MBP).
Methods
Sera were tested by ELISA for ASCA IgG and IgA, anti-OmpC, anti-CBir1 and ANCA in 76 patients with AS alone, 77 patients with AS-IBD and 48 patients with MBP. Antibody positivity rates, median quantitative antibody levels and the proportion of patients with antibody levels in the 4th quartile of a normal distribution were compared between the three groups of patients.
Results
Patients with AS alone demonstrated higher anti-CBir1 antibody positivity rates and median antibody levels than MBP patients. Anti-CBir1 positivity in AS was associated with elevation of acute phase reactants. AS-IBD patients demonstrated elevated responses when compared to AS alone for ASCA, anti-OmpC and anti-CBir1. Quartile analysis confirmed the findings.
Conclusions
These data suggest that adaptive immune responses to microbial antigens occur in AS patients without clinical IBD and support the theory of mucosal dysregulation as a mechanism underlying the pathophysiology of AS.
doi:10.1186/ar4350
PMCID: PMC3978579  PMID: 24286190
7.  CERVICAL VERTEBRAL SQUARING IN PATIENTS WITHOUT SPONDYLOARTHRITIS 
The Journal of rheumatology  2012;39(9):1900.
doi:10.3899/jrheum.120322
PMCID: PMC3461321  PMID: 22942307
Spondyloarthritis; squaring; vertebrae
8.  Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci 
Nature genetics  2013;45(7):730-738.
Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.
doi:10.1038/ng.2667
PMCID: PMC3757343  PMID: 23749187
9.  A Multidimensional Model of Fatigue in Patients with Rheumatoid Arthritis 
The Journal of rheumatology  2012;39(9):1807-1813.
Objective
To evaluate a multidimensional model testing disease activity, mood disturbance, and poor sleep quality as determinants of fatigue in patients with rheumatoid arthritis (RA).
Method
The data of 106 participants were drawn from baseline of a randomized comparative efficacy trial of psychosocial interventions for RA. Sets of reliable and valid measures were used to represent model constructs. Structural equation modeling was used to test the direct effects of disease activity, mood disturbance, and poor sleep quality on fatigue, as well as the indirect effects of disease activity as mediated by mood disturbance and poor sleep quality.
Results
The final model fit the data well, and the specified predictors explained 62% of the variance in fatigue. Higher levels of disease activity, mood disturbance, and poor sleep quality had direct effects on fatigue. Further, disease activity was indirectly related to fatigue through its effects on mood disturbance, which, in turn, was related to poor sleep quality. Mood disturbance also indirectly influenced fatigue through poor sleep quality.
Conclusion
The findings from this study confirmed the importance of a multidimensional framework in evaluating the contribution of disease activity, mood disturbance, and sleep quality to fatigue in RA using a structural equation approach. Mood disturbance and poor sleep quality played major roles in explaining fatigue along with patient-reported disease activity.
doi:10.3899/jrheum.111068
PMCID: PMC3735362  PMID: 22660801
Rheumatoid arthritis; Fatigue; Mood; Sleep disorders; Psychological factors
10.  Inflammatory Back Pain 
doi:10.1016/j.rdc.2012.09.002
PMCID: PMC3501982  PMID: 23083751
11.  A Randomized, Double-Blind, Placebo-Controlled Trial of Recombinant Human Relaxin in the Treatment of Systemic Sclerosis with Diffuse Scleroderma 
Arthritis and rheumatism  2009;60(4):1102-1111.
Background/Purpose
A phase II randomized controlled trial of recombinant human relaxin suggested that 25 ug/kg/day was safe and clinically effective in improving skin disease and functional disability in scleroderma. We report the results of a large randomized, double-blind, placebo-controlled clinical trial comparing placebo with recombinant human relaxin, 10 ug/kg of body weight per day and 25 ug/kg per day, given for 24 weeks in patients with stable, diffuse, moderate to severe scleroderma (SSc).
Methods
Men and women 18 to 70 years of age with diffuse SSc, disease duration ≤ 5 years since the onset of the first non-Raynaud sign or symptom, a baseline modified Rodnan skin score (MRSS) of 20 or greater, or at least 16 if truncal involvement was present. Recombinant human relaxin (10 or 25 ug/kg/day), or placebo was administered for 24 weeks as a continuous subcutaneous infusion and there was a follow-up safety visit at week 28.
Results
The primary outcome measure, the MRSS, was similar between the 3 groups at baseline and at weeks 4, 12, and 24 (P=NS). Secondary outcomes such as functional disability were similar in all 3 groups and the forced vital capacity significantly decreased in the relaxin groups (p< 0.04). The discontinuation of relaxin (both doses) at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as either doubling of baseline serum creatinine, renal crisis, or grade 3 or 4 hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo (p=0.04).
Conclusion
Recombinant relaxin was not significantly better than placebo in improving total skin score, pulmonary function, or functional disability in patients with diffuse SSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.
doi:10.1002/art.24380
PMCID: PMC3711466  PMID: 19333948
12.  Airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? 
Arthritis and Rheumatism  2011;64(6):1756-1761.
Objective
To evaluate the presence of pulmonary abnormalities in subjects with rheumatoid arthritis (RA)-related autoantibody (Ab) positivity without inflammatory arthritis (IA).
Methods
42 subjects without IA but with elevations of anti-cyclic citrullinated peptide antibodies and/or 2 or more rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 Ab(−) controls and 12 patients with early established seropositive RA (<1 year duration) underwent spirometry and high-resolution computed tomographic (HRCT) lung imaging.
Results
The median age of Ab(+) subjects was 54 years-old, 52% were female and 38% were smokers (not significantly different than Ab(−) controls). No Ab(+) subject had IA on joint examination. On HRCT, 76% of Ab(+) subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities and air trapping, compared to 33% of Ab(−) controls (p=0.005). The Ab(+) subjects had similar prevalence and type of lung abnormalities compared to patients with early RA. Two Ab(+) subjects with airways disease developed IA classifiable as articular RA ~13 months after lung evaluation.
Conclusion
Airways abnormalities that are consistent with inflammation are common in Ab(+) subjects without IA, and similar to airways abnormalities seen in early RA. These findings suggest that the lung may be an early site of autoimmune-related injury, and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA.
doi:10.1002/art.34344
PMCID: PMC3319006  PMID: 22183986
Rheumatoid arthritis; etiology; autoantibodies; preclinical; lung disease
13.  Sex chromosome Aneuploides among Men with Systemic Lupus Erythematosus 
Journal of Autoimmunity  2011;38(2-3):J129-J134.
About 90% of patients with systemic lupus erythematosus (SLE) are female. We hypothesize that the number of X chromosomes, not sex, is a determinate of risk of SLE. Number of X chromosomes was determined by single nucleotide typing and then confirmed by karyotype or fluorescent in situ hybridization in a large group of men with SLE. Presence of an sry gene was assessed by rtPCR. We calculated 96% confidence intervals using the Adjusted Wald method, and used Bayes’ theorem to estimate the prevalence of SLE among 47,XXY and 46,XX men. Among 316 men with SLE, 7 had 47,XXY and 1 had 46,XX. The rate of Klinefelter’s syndrome (47,XXY) was statistically different from that found in control men and from the known prevalence in the population. The 46,XX man had an sry gene, which encodes the testes determining factor, on an X chromosome as a result of an abnormal crossover during meiosis. In the case of 46,XX, 1 of 316 was statistically different from the known population prevalence of 1 in 20,000 live male births. A previously reported 46,XX man with SLE had a different molecular mechanism in which there were no common gene copy number abnormalities with our patient. Thus, men with SLE are enriched for conditions with additional X chromosomes. Especially since 46,XX men are generally normal males, except for infertility, these data suggest the number of X chromosomes, not phenotypic sex, is responsible for the sex bias of SLE.
doi:10.1016/j.jaut.2011.10.004
PMCID: PMC3309073  PMID: 22154021
Systemic lupus erythematosus; Klinefelter’s syndrome; male 46; XX; female bias; X chromosome
14.  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
15.  The Contribution of Pain and Depression to Self-Reported Sleep Disturbance in Patients with Rheumatoid Arthritis 
Pain  2011;153(1):107-112.
The objective of this paper is to assess the contribution of disease activity, pain, and psychological factors to self-reported sleep disturbance in patients with rheumatoid arthritis (RA), and to evaluate whether depression mediates the effects of pain on sleep disturbance. The sample included 106 patients with confirmed RA participated in an assessment of their disease activity, pain, psychological functioning, and sleep disturbance during a baseline evaluation prior to participating in a prospective study to help them manage their RA. Self-measures included the Rapid Assessment of Disease Activity in Rheumatology (RADAR), the SF-36 Pain Scale, the Helplessness and Internality Subscales of the Arthritis Helplessness Index (AHI), the Active and Passive Pain Coping Scales of the Pain Management Inventory (PMI), the Center for Epidemiological Studies Depression Scale (CES-D), and the Pittsburgh Sleep Quality Index (PSQI). Hierarchical multiple regression analysis confirmed that higher income, pain, internality, and depression contributed independently to higher sleep disturbance. A mediational analysis demonstrated that depression acted as a significant mechanism through which pain contributed to sleep disturbance. Cross-sectional findings indicate that pain and depression play significant roles in self-reported sleep disturbance among patients with RA. The data suggest the importance of interventions that target pain and depression to improve sleep in this medical condition.
doi:10.1016/j.pain.2011.09.024
PMCID: PMC3245817  PMID: 22051047
pain; depression; sleep disturbance; rheumatoid arthritis
16.  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
17.  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
18.  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
19.  Cost Effectiveness of Different Treatment Strategies in the Treatment of Patients with Moderate to Severe Rheumatoid Arthritis in China 
PLoS ONE  2012;7(10):e47373.
Background
To analyse the cost-effectiveness of traditional disease-modifying anti-rheumatic drugs (tDMARDs) compared to biological therapies from the perspective of Chinese society.
Methodology/Principal Findings
A mathematical model was developed by incorporating the clinical trial data and Chinese unit costs and treatment sequences from a lifetime perspective. Hypothetical cohorts with moderate to severe RA were simulated. The primary outcome measure–quality-adjusted life years (QALYs)–was derived from disease severity (HAQ scores). Primary analysis included drug costs, monitoring costs, and other costs. Probabilistic and one-way sensitivity analyses were performed. Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALYs than tDMARDs alone or TNF antagonists plus DMARDs. In comparison with tDMARDs, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab, and adalimumab without rituximab were $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, for etanercept, infliximab, and adalimumab with rituximab. No biotherapy was cost-effective under the willingness to pay threshold when the threshold was 3 times the per capita GDP of China. When 3 times the per capita GDP of Shanghai used as the threshold, infliximab and rituximab could yield nearly 90% cost-effective simulations in probabilistic sensitivity analysis.
Conclusions/Significance
tDMARD was the most cost-effective option in the Chinese healthcare setting. In some relatively developed regions in China, infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA.
doi:10.1371/journal.pone.0047373
PMCID: PMC3467255  PMID: 23056637
20.  Neuroimaging evidence of white matter inflammation in newly diagnosed Systemic Lupus Erythematosus 
Arthritis and rheumatism  2011;63(10):3048-3057.
Objective
Systemic lupus erythematosus (SLE) with central nervous system (CNS) involvement is frequent and can have high morbidity. The primary pathophysiology of SLE in the CNS is thought to be inflammation secondary to autoantibody-mediated vasculitis. Neuroimaging studies have reported hypometabolism (impending cell failure) and atrophy (late-stage pathology), but not inflammation. We used a validated index of SLE-related disease activity as a regressor for positron emission tomographic (PET) images of glucose uptake to detect the presence and regional distribution of inflammation (hypermetabolism) and tissue failure, apoptosis or atrophy (hypometabolism).
Methods
Eighty-five newly diagnosed SLE patients without focal neurological symptoms were studied. Disease activity was quantified using the SELENA SLE Disease Activity Index (SS). 18Fluoro-deoxy-glucose (FDG) PET images were analyzed by visual inspection and as group statistical parametric images using the SS score as the analysis regressor.
Results
SS-correlated increases in glucose uptake were found throughout the white matter, most marked in heavily myelinated tracts. SS-correlated decreases were found in frontal and parietal cortex, in a pattern similar to that seen by visual inspection and in prior reports of hypometabolism.
Conclusion
We interpret the SS-correlated increases in glucose consumption as potential evidence of inflammation, in keeping with prior reports of hypermetabolism in inflammatory disorders. To our knowledge, this is the first imaging evidence of SLE-induced CNS inflammation in an SLE inception cohort. The dissociation between 18FDG uptake characteristics, spatial distribution, and correlation with disease activity argues that glucose hyper- and hypometabolism reflect fundamentally different aspects of the pathophysiology of CNS SLE.
doi:10.1002/art.30458
PMCID: PMC3167945  PMID: 21618460
systemic lupus erythematosus; positron emission tomography; glucose metabolism; SLEDAI; inflammation
21.  Multiple Autoantibodies Display Association with Lymphopenia, Proteinuria, and Cellular Casts in a Large, Ethnically Diverse SLE Patient Cohort 
Autoimmune Diseases  2012;2012:819634.
Purpose. This study evaluates high-throughput autoantibody screening and determines associated systemic lupus erythematosus (SLE) clinical features in a large lupus cohort. Methods. Clinical and demographic information, along with serum samples, were obtained from each SLE study participant after appropriate informed consent. Serum samples were screened for 10 distinct SLE autoantibody specificities and examined for association with SLE ACR criteria and subcriteria using conditional logistic regression analysis. Results. In European-American SLE patients, autoantibodies against 52 kD Ro and RNP 68 are independently enriched in patients with lymphopenia, anti-La, and anti-ribosomal P are increased in patients with malar rash, and anti-dsDNA and anti-Sm are enriched in patients with proteinuria. In African-American SLE patients, cellular casts associate with autoantibodies against dsDNA, Sm, and Sm/nRNP. Conclusion. Using a high-throughput, bead-based method of autoantibody detection, anti-dsDNA is significantly enriched in patienets with SLE ACR renal criteria as has been previously described. However, lymphopenia is associated with several distinct autoantibody specificities. These findings offer meaningful information to allow clinicians and clinical investigators to understand which autoantibodies correlate with select SLE clinical manifestations across common racial groups using this novel methodology which is expanding in clinical use.
doi:10.1155/2012/819634
PMCID: PMC3439936  PMID: 22988489
22.  An Evaluation of a Biopsychosocial Framework for Health-Related Quality of Life and Disability in Rheumatoid Arthritis 
Objective
To examine the relationships between physical, psychological, and social factors and health-related quality of life (HRQOL) and disability in rheumatoid arthritis (RA).
Methods
A sample of 106 patients with rheumatoid arthritis (RA) completed measures of self-reported disease activity and psychosocial functioning, including coping, personal mastery, social network, perceived stress, illness beliefs, the SF-36 and Health Assessment Questionnaire Disability Index (HAQ-DI). In addition, physician-based assessment of disease activity using the Disease Activity Scale (DAS 28) was obtained. Hierarchical multiple regression analyses were used to evaluate the relationships between psychosocial factors and scores on the SF-36 and HAQ-DI.
Results
Lower self-reported disease activity and higher active coping were significantly related to SF-36 physical functioning scores, whereas lower self-reported disease activity, higher personal mastery, and lower perceived stress contributed to higher SF-36 mental health functioning. Higher self-reported disease activity and lower helplessness were associated with greater disability as indexed by the HAQ-DI. The DAS 28 was unrelated to these outcomes.
Conclusions
The findings highlight the importance of targeting psychological factors to enhance HRQOL in the clinical management of RA patients.
doi:10.1016/j.jpsychores.2011.01.008
PMCID: PMC3139906  PMID: 21767687
Health-related quality of life; psychological factors; rheumatoid arthritis
23.  New insights into the role and mechanism of macrophage migration inhibitory factor in steroid-resistant patients with systemic lupus erythematosus 
Arthritis Research & Therapy  2012;14(3):R103.
Introduction
Glucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE). However, some patients do not achieve an effective response with GC treatment, creating an obstacle to the remission of SLE. Identification of the underlying mechanisms responsible for steroid resistance can be significant. Macrophage migration inhibitory factor (MIF) arouses our interest because of its reciprocal relationship with GCs. In the present study, we investigated for the first time whether MIF correlated with steroid resistance in SLE and explored potential mechanisms of action.
Methods
Sixty-two patients with SLE (40 steroid sensitive and 22 steroid resistant) and 21 normal controls were recruited. Serum levels of MIF were measured by ELISA. Cytosolic MIF and IκB expression in peripheral blood mononuclear cells (PBMCs) were determined by western blotting. The electrophoretic mobility shift assay was assessed by NF-κB in nuclear aliquots. Gene silencing was applied to reduce expression of MIF in PBMCs in steroid-resistant patients. PBMCs obtained from steroid-sensitive patients were treated with recombinant human MIF of different concentrations.
Results
MIF levels in serum and PBMCs were higher in steroid-resistant patients compared with steroid-sensitive patients and controls. In contrast to the steroid-sensitive group, NF-κB levels were significantly higher and IκB levels lower in steroid-resistant patients. After MIF gene silencing, IκB levels in cells from steroid-resistant patients were increased. In steroid-sensitive patients, a decrease in IκB levels and an increase in NF-κB expression from baseline were detected in PBMCs treated with a higher concentration of recombinant human MIF. Treatment with recombinant human MIF did not regulate expression of IκB and NF-κB in PBMCs from patients treated with an anti-MIF monoclonal antibody.
Conclusions
Our results indicated that MIF may play a role in the formation of steroid resistance in SLE by affecting the NF-κB/IκB signaling cascade. As a regulator of glucocorticoid sensitivity, MIF may be a potential target for steroid sparing.
doi:10.1186/ar3828
PMCID: PMC3446480  PMID: 22551315
24.  Whole-blood Gene Expression Profiling in Ankylosing Spondylitis Shows Upregulation of Toll-like Receptor 4 and 5 
The Journal of rheumatology  2010;38(1):87-98.
Objective
To identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation.
Methods
We investigated PBC samples of 16 patients with AS and 14 matched controls, in addition to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) samples utilizing Illumina Human Ref-8 BeadChips. Candidate genes were confirmed using quantitative PCR. Subsequently, these genes were also validated in a separate sample of 27 patients with AS [before and after antitumor necrosis factor (anti-TNF) treatment] and 27 matched controls.
Results
We identified 83 differentially expressed transcripts between AS patients and controls. This gene list was filtered through the lists of differentially expressed transcripts in SLE and SSc, which resulted in identification of 52 uniquely dysregulated transcripts in AS. Many of the differentially expressed genes belonged to Toll-like receptor (TLR) and related pathways. TLR4 and TLR5 were the only dysregulated TLR subtypes among AS patients. We confirmed the overexpression of TLR4 and TLR5 in AS patients in comparison to controls (p = 0.012 and p = 0.006, respectively) and SLE (p = 0.002, p = 0.008) using quantitative PCR in the same sample. Similarly, TLR4 (p = 0.007) and TLR5 (p = 0.012) were significantly upregulated among the AS patients before anti-TNF treatment in the confirmatory sample. TLR4 (p = 0.002) and TLR5 (p = 0.025) decreased significantly after anti-TNF treatment.
Conclusion
PBC gene expression profiling in AS shows an upregulation of TLR4 and TLR5. This supports the importance of TLR subtypes in the pathogenesis of AS that are responsible for the immune response to Gram-negative bacteria.
doi:10.3899/jrheum.100469
PMCID: PMC3014385  PMID: 20952467
ANKYLOSING SPONDYLITIS; TOLL-LIKE RECEPTORS; IMMUNE SYSTEM; AUTOIMMUNITY; BACTERIA; GENE EXPRESSION PROFILING
25.  The Lupus Family Registry and Repository 
Rheumatology (Oxford, England)  2010;50(1):47-59.
The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR’s effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.
doi:10.1093/rheumatology/keq302
PMCID: PMC3307518  PMID: 20864496
Systemic lupus erythematosus; Registry; Repository; Autoimmune diseases; Genetics; Heritability; Genome-wide association studies; Linkage analysis; Minorities; Women

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