Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

OBJECTIVE: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain. METHODS: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI. RESULTS: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively. CONCLUSIONS: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

Chronic back pain in first-degree relatives (FDRs) of patients with ankylosing spondylitis: predictive value of HLA-B27 and persistence of inflammatory back pain over time.

BACKGROUND/PURPOSE: First-degree relatives (FDRs) of patients with ankylosing spondylitis (AS) may be at high risk of spondyloarthritis. We examined the frequency, characteristics of chronic back pain (CBP), associated features, persistence of symptoms, and HLA-B27 allele frequency in FDRs of AS patients, also comparing those FDRs with participants in NHANES 2009-2010 with CBP. METHODS: 399 FDRs of AS probands were divided into: (1) No CBP (subjects >40 years old at study visit without CBP) (n=162); (2) NICBP (non-inflammatory CBP) (n=82), and (3) CIBP (inflammatory CBP) (n=155). White FDRs with CBP were compared with 772 participants in NHANES 2009-2010 with CBP. FDRs were invited to return for reassessment. RESULTS: FDRs with CIBP had earlier onset of CBP than those with NICBP (p<0.001) and had higher frequency of heel pain than those without CBP (p=0.002). HLA-B27 occurred in 57% of FDRs with CIBP vs 39.6% of those without CBP (p=0.005, OR=1.9). Of 23 patients with CIBP at baseline re-evaluated 67.04±31.02 months later, 16 (73%) still had CIBP, whereas 4 (31%) of 13 NICBP patients seen 61.23±31.84 months later remained symptomatic. CONCLUSION: CIBP in FDRs of AS patients is HLA-B27-associated, has earlier onset and tends to persist compared to NICBP.

The changing profile of ankylosing spondylitis in the biologic era.

OBJECTIVE: To compare disease characteristics, comorbidities, and medication utilization of 1141 patients with ankylosing spondylitis (AS) with short (< 20 years) and long (≥ 20 years) disease duration enrolled in the Prospective Study of Outcomes in AS (PSOAS) study over three different periods of time and followed longitudinally. METHODS: Study visits were carried out every 6 months examining disease activity (Bath AS Disease Activity Index (BASDAI), C-reactive protein, erythrocyte sedimentation rate), functional impairment, depression, and medication utilization as well as radiographic severity. Groups were compared with regression models using generalized estimating equation, linear, and Poisson regressions after adjusting for sites and for patients withdrawing from the study at less than 2 years follow-up. RESULTS: Overall, AS patients with long disease duration were more likely to be married, white, receiving disability, and to be with higher functional impairment and radiographic severity, more uveitis, diabetes, hypertension, cardiovascular disease, and osteoporosis, and with less nonsteroidal anti-inflammatory drug (NSAID) and more opioid use than those with short disease duration. Current smoking decreased between 2002 and 2019 regardless of disease duration. Lower baseline NSAID and methotrexate/sulfasalazine use and higher TNF inhibitor usage were seen only in those with shorter disease duration, though NSAID use and functional impairment decreased over time in both groups. Disease activity, depression scores, and NSAID use decreased and anti-TNF use increased in those followed > 8 years. CONCLUSIONS: Patients with AS enrolling in this multicenter longitudinal cohort have different disease profiles and medication utilization over time, perhaps reflecting innovations in treatment and increasing disease awareness. Key Points • The use of NSAIDs, nonbiologic DMARDs, and prednisone has decreased over the past 16 years in patients with AS. • The use of anti-TNF agents has dramatically increased. • In treated patients, disease activity, depression scores, and functional impairment have decreased over time.

Harmonization, data management, and statistical issues related to prospective multicenter studies in Ankylosing spondylitis (AS): Experience from the Prospective Study Of Ankylosing Spondylitis (PSOAS) cohort.

Ankylosing spondylitis (AS) is characterized by inflammation of the spine and sacroiliac joints causing pain and stiffness and, in some patients, ultimately new bone formation, and progressive joint ankyloses. The classical definition of AS is based on the modified New York (mNY) criteria. Limited data have been reported regarding data quality assurance procedure for multicenter or multisite prospective cohort of patients with AS. Since 2002, 1272 qualified AS patients have been enrolled from five sites (4 US sites and 1 Australian site) in the Prospective Study Of Ankylosing Spondylitis (PSOAS). In 2012, a Data Management and Statistical Core (DMSC) was added to the PSOAS team to assist in study design, establish a systematic approach to data management and data quality, and develop and apply appropriate statistical analysis of data. With assistance from the PSOAS investigators, DMSC modified Case Report Forms and developed database in Research Electronic Data Capture (REDCap). DMSC also developed additional data quality assurance procedure to assure data quality. The error rate for various forms in PSOAS databases ranged from 0.07% for medications data to 1.1% for arthritis activity questionnaire-Global pain. Furthermore, based on data from a sub study of 48 patients with AS, we showed a strong level (90.0%) of agreement between the two readers of X-rays with respect to modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). This paper not only could serve as reference for future publications from PSOAS cohort but also could serve as a basic guide to ensuring data quality for multicenter clinical studies.

A multiple imputation method based on weighted quantile regression models for longitudinal censored biomarker data with missing values at early visits.

BACKGROUND: In patient-based studies, biomarker data are often subject to left censoring due to the detection limits, or to incomplete sample or data collection. In the context of longitudinal regression analysis, inappropriate handling of these issues could lead to biased parameter estimates. We developed a specific multiple imputation (MI) strategy based on weighted censored quantile regression (CQR) that not only accounts for censoring, but also missing data at early visits when longitudinal biomarker data are modeled as a covariate. METHODS: We assessed through simulation studies the performances of developed imputation approach by considering various scenarios of covariance structures of longitudinal data and levels of censoring. We also illustrated the application of the proposed method to the Prospective Study of Outcomes in Ankylosing spondylitis (AS) (PSOAS) data to address the issues of censored or missing C-reactive protein (CRP) level at early visits for a group of patients. RESULTS: Our findings from simulation studies indicated that the proposed method performs better than other MI methods by having a higher relative efficiency. We also found that our approach is not sensitive to the choice of covariance structure as compared to other methods that assume normality of biomarker data. The analysis results of PSOAS data from the imputed CRP levels based on our method suggested that higher CRP is significantly associated with radiographic damage, while those from other methods did not result in a significant association. CONCLUSION: The MI based on weighted CQR offers a more valid statistical approach to evaluate a biomarker of disease in the presence of both issues with censoring and missing data in early visits.

Opioid Analgesic Use in Patients with Ankylosing Spondylitis: An Analysis of the Prospective Study of Outcomes in an Ankylosing Spondylitis Cohort.

OBJECTIVE: Opioid analgesics may be prescribed to ankylosing spondylitis (AS) patients with pain that is unresponsive to antirheumatic treatment. Our study assessed factors associated with opioid usage in AS. METHODS: A prospective cohort of 706 patients with AS meeting modified New York criteria followed at least 2 years underwent comprehensive clinical evaluation of disease activity and functional impairment. These were assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI). Radiographic severity was assessed by the Bath Ankylosing Spondylitis Radiology Index and modified Stokes Ankylosing Spondylitis Scoring System. Medications taken concurrently with opioids, as well as C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR), were determined at each study visit, performed every 6 months. Analyses were carried out at baseline, and longitudinal multivariable models were developed to identify factors independently associated with chronic and intermittent opioid usage over time. RESULTS: Factors significantly associated with opioid usage, especially chronic opioid use, included longer disease duration, smoking, lack of exercise, higher disease activity (BASDAI) and functional impairment (BASFI), depression, radiographic severity, and cardiovascular disease. Patients taking opioids were more likely to be using anxiolytic, hypnotic, antidepressant, and muscle relaxant medications. Multivariable analysis underscored the association with smoking, older age, antitumor necrosis factor agent use, and psychoactive drugs, as well as with subjective but not objective determinants of disease activity. CONCLUSION: Opioid usage was more likely to be associated with subjective measures (depression, BASDAI, BASFI) than objective measures (CRP, ESR), suggesting that pain in AS may derive from sources other than spinal inflammation alone.

Ethnicity and disease severity in ankylosing spondylitis a cross-sectional analysis of three ethnic groups.

The purpose of this study is to compare disease severity in ankylosing spondylitis (AS) in three ethnic groups. We assessed 925 AS patients (57 Blacks, 805 Whites, 63 Latinos) enrolled in the longitudinal Prospective Study of Outcomes in AS (PSOAS) for functional impairment, disease activity, and radiographic severity. Comparisons of clinical characteristics and HLA-B27 frequency for each group were performed, in two multivariable regression models, we compared the baseline Bath Ankylosing Spondylitis Radiographic Index (BASRI) and modified Stokes Ankylosing Spondylitis Spine Score (mSASSS) by ethnicity, adjusting for covariates. Blacks had greater functional impairment (Bath Ankylosing Spondylitis Functional Index) (median 62.5 vs. 27.8 in Whites and 38.1 in Latinos; p < 0.0001); higher disease activity (Bath Ankylosing Spondylitis Disease Activity Index), (median 5.9 vs. 3.5 in Whites and 4.5 in Latinos; p < 0.0001), erythrocyte sedimentation rate (median 27.0 in Blacks vs. 10.0 in Whites and 17.0; p < 0.0001), and C-reactive protein levels (median 1.2 vs. 0.4 mg/dL in Whites and 0.9 in Latinos; p < 0.0001). Baseline BASRI and mSASSS were higher in Blacks (mean 9.5 and median 38.2, respectively) compared to Whites (7.3 and 6.4) and Latinos (7.3 and 8.1), (p = 0.004, 0.007), respectively, more significant as disease duration increased. HLA-B27 occurred in 62.5% of Blacks, 85.3% of Whites, and 86.7% of Latinos (p < 0.0001). On multivariable analysis, higher BASRI and mSASSS were associated with Black ethnicity, after adjusting for disease duration and gender as well as TNF inhibitor (TNFi) usage, smoking status, or education level. Blacks with AS have more severe disease compared to either Whites or Latinos.

New population-based reference values for spinal mobility measures based on the 2009-2010 National Health and Nutrition Examination Survey.

OBJECTIVE: To report population-based percentile reference values for selected spinal mobility measures in a nationally representative sample of 5,001 US adults ages 20-69 years who were examined in the 2009-2010 US National Health and Nutrition Examination Survey (NHANES). METHODS: Occiput-to-wall distance (OWD), thoracic expansion (TE), and anterior lumbar flexion (ALF; by modified Schober test) were measured by trained examiners in a standardized manner. TE was measured at the xiphisternal level, while the lower reference point for ALF was a line marked at the level of the superior margin of the lateral iliac crests. We report reference values based on the 95th percentile for the OWD and the 5th percentile for TE and ALF, as well as other summary statistics for these measures, in the study population. RESULTS: An OWD of >0 was present in 3.8% of the participants, while 8.8% of them had out-of-range values for TE based on the commonly used threshold of 2.5 cm. The 95th percentile of the OWD measurement was 0, while the 5th percentile for TE and ALF were 1.9 cm and 2 cm, respectively. The spinal measures were significantly associated with sex, age, ethnicity, height, and body mass index (BMI). Exclusion of individuals with severe obesity (BMI >35 kg/m(2) ) changed the proposed reference values for TE and ALF to 2.2 cm and 1.9 cm, respectively. CONCLUSION: We verified a reference value of 0 for the OWD in the general population. Using the reported population-based percentile values, new reference values for TE and ALF can be derived.

Psychological correlates of self-reported disease activity in ankylosing spondylitis.

OBJECTIVE: To investigate the role of psychological variables in self-reported disease activity in patients with ankylosing spondylitis (AS), while controlling for demographic and medical variables. METHODS: Patients with AS (n = 294) meeting modified New York criteria completed psychological measures evaluating depression, resilience, active and passive coping, internality, and helplessness. Demographic, clinical, and radiologic data were also collected. Univariate and multivariate analyses were completed to determine the strength of the correlation of psychological variables with disease activity, as measured by the Bath AS Disease Activity Index (BASDAI). RESULTS: In the multivariate regression analysis, the psychological variables contributed significantly to the variance in BASDAI scores, adding an additional 33% to the overall R-square beyond that accounted for by demographic and medical variables (combined R-square 18%). Specifically, arthritis helplessness and depression accounted for the most significant portion of the variance in BASDAI scores in the final model. CONCLUSION: Arthritis helplessness and depression accounted for significant variability in self-reported disease activity beyond clinical and demographic variables in patients with AS. These findings have important clinical implications in the treatment and monitoring of disease activity in AS, and suggest potential avenues of intervention.

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Psychological correlates of self-reported functional limitation in patients with ankylosing spondylitis.

INTRODUCTION: Functional status is an integral component of health-related quality of life in patients with ankylosing spondylitis (AS). The purpose of this study was to investigate the role of psychological variables in self-reported functional limitation in patients with AS, while controlling for demographic and medical variables. METHODS: 294 AS patients meeting modified New York Criteria completed psychological measures evaluating depression, resilience, active and passive coping, internality and helplessness at the baseline visit. Demographic, clinical, and radiologic data were also collected. Univariate and multivariate analyses were completed to determine the strength of correlation of psychological variables with functional limitation, as measured by the Bath AS Functional Index (BASFI). RESULTS: In the multivariate regression analysis, the psychological variables contributed significantly to the variance in BASFI scores, adding an additional 24% to the overall R-square beyond that accounted by demographic and medical variables (R-square 32%), resulting in a final R-square of 56%. Specifically, arthritis helplessness, depression and passive coping beside age, ESR and the Bath AS Radiograph Index accounted for a significant portion of the variance in BASFI scores in the final model. CONCLUSIONS: Arthritis helplessness, depression, and passive coping accounted for significant variability in self-reported functional limitation beyond demographic and clinical variables in patients with AS. Psychological health should be examined and accounted for when assessing functional status in the AS patients.

Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations.

INTRODUCTION: Systemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets. METHODS: Plasma from 444 SSc patients and 216 healthy controls was obtained from the Scleroderma Family Registry and University of Texas Rheumatology Division. Patients were classified according to the presence of ACAs, ATAs, ARAs, or none of the above (antibody-negative). Levels of 13 cytokines were determined using multiplex assays. RESULTS: Compared with females, healthy control males had higher plasma levels of IL-2 (P = 0.008), IL-5 (P = 0.01) and IL-8 (P = 0.01). In addition, in controls, IL-6 (P = 0.02) and IL-17 (P = 0.01) levels increased with advancing age. After adjusting for age and gender, SSc patients had higher circulating levels of TNFalpha (P < 0.0001), IL-6 (P < 0.0001), and IFNgamma (P = 0.05) and lower IL-17 (P = 0.0005) and IL-23 (P = 0.014). Additional analyses demonstrated that disease duration also influenced these cytokine profiles. IL-6 was elevated in ATA-positive and ARA-positive patients, but not in ACA-positive patients. IL-8 was uniquely increased in the ATA-positive subset while both ATA-positive and ACA-positive subsets had elevated IFNgamma and IL-10. IL-5 was only significantly increased in the ACA-positive subset. Lastly, patients with interstitial lung disease had elevated IL-6 and patients with pulmonary hypertension had elevated IL-6 and IL-13. CONCLUSIONS: Plasma cytokine profiles differ in SSc patients based on the presence of SSc-associated autoantibodies. Plasma cytokine profiles in SSc patients may also be affected by disease duration and the pattern of internal organ involvement.

Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial.

OBJECTIVE: To evaluate the efficacy and safety of golimumab in patients with ankylosing spondylitis (AS) in the GO-RAISE study. METHODS: Patients with active AS, a Bath AS Disease Activity Index (BASDAI) score > or =4, and a back pain score of > or =4 were randomly assigned in a 1.8:1.8:1 ratio to receive subcutaneous injections of golimumab (50 mg or 100 mg) or placebo every 4 weeks. The primary end point was the proportion of patients with at least 20% improvement in the ASsessment in AS (ASAS20) criteria at week 14. RESULTS: At randomization, 138, 140, and 78 patients were assigned to the 50-mg, 100-mg, and placebo groups, respectively. After 14 weeks, 59.4%, 60.0%, and 21.8% of patients, respectively, were ASAS20 responders (P < 0.001). A 40% improvement in the ASAS criteria at week 24 occurred in 43.5%, 54.3%, and 15.4% of patients, respectively. Patients receiving golimumab also showed significant improvement in the physical and mental component summary scores of the Short Form 36 Health Survey, the Jenkins Sleep Evaluation Questionnaire score, the BASDAI score, and the Bath AS Functional Index score, but not the Bath AS Metrology Index score. Through week 24, 85.6% of golimumab-treated patients and 76.6% of patients in the placebo group had > or =1 adverse event, and 5.4% and 6.5% of patients, respectively, had > or =1 serious adverse event. Eight golimumab-treated patients and 1 placebo-treated patient had markedly abnormal liver enzyme values (> or =100% increase from baseline and a value >150 IU/liter), which were transient. CONCLUSION: Golimumab was effective and well tolerated in a large cohort of patients with AS during a 24-week study period.