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The Patient-Reported Outcomes Measurement Information System 29-Item Health Profile (PROMIS-29) is a generic measure of health-related quality of life that is not well-studied in Ankylosing Spondylitis (AS) patients. Our objective was to investigate the reliability and validity of the PROMIS-29 in AS. About 169 consecutive AS patients were enrolled from 2017 to 2022 with 167/169 patients fully completing the PROMIS-29 in this cross-sectional study. Test-retest reliability and internal consistency was assessed using intraclass correlation coefficients (ICC) and Cronbach alpha, respectively. We studied structural validity with confirmatory factor analysis (CFA) of our hypothesized and general population models. We evaluated model fit by Chi-squared goodness-of-fit-test (χ2), comparative fit index, and root mean square error of approximation. A χ2 test was used to compare nested models. PROMIS-29 convergent validity was studied by Spearman correlation coefficients with AS-legacy measures. PROMIS-29 domains showed good test-retest reliability (intraclass correlation coefficients (ICC)â >â 0.7) and excellent internal consistency with Cronbach alphaâ >â 0.9 in all subscales. CFA of only the general population model met our model fit cutoffs (χ2 goodness-of-fit P-value of 0.21, comparative fit index of 0.99, and root mean square error of approximation of 0.05). Furthermore, a nested χ2 test was not significantly different between our hypothesized (full) and general (reduced) model [χ2 (1)â =â 0.754, Pâ >â .38]. AS legacy measures showed a strong correlation (rho > |0.7|) with the extracted physical health factor. The PROMIS-29 demonstrated good reliability and construct validity in AS patients with the general population model. Further study is required to determine its clinical and research utility in AS patients.
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Espondilite Anquilosante , Humanos , Qualidade de Vida , Estudos Transversais , Reprodutibilidade dos Testes , Psicometria , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: To examine the association of multimorbidity phenotypes at baseline with disease activity and functional status over time in ankylosing spondylitis (AS). METHODS: Patient-reported AS morbidities (comorbidities, N = 28 and extra-musculoskeletal manifestations, EMMs, N = 3) within 3 years of enrollment with a prevalence ≥1 %, were included from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) cohort. We defined multimorbidity as ≥2 morbidities (MM2+) and substantial multimorbidity as ≥5 morbidities (MM5+). Multimorbidity clusters or phenotypes were identified using K-median clustering. Disease activity (ASDAS-CRP) and functional status (BASFI) measures were collected every 6 months. Generalized estimating equation method was used to examine the associations of multimorbidity counts and multimorbidity clusters with measures of disease activity and functional status over time. RESULTS: Among 1,270 AS patients (9,885 visits) with a median follow-up of 2.9 years (IQ range: 1.0-6.8 years), the prevalence of MM2+ and MM5+ was 49 % and 9 % respectively. We identified five multimorbidity clusters: depression (n = 321, 25 %), hypertension (n = 284, 22 %), uveitis (n = 274, 22 %), no morbidities (n = 238, 19 %), and miscellaneous (n = 153, 12 %). Patients in the depression cluster were more likely to be female and had significantly more morbidities and worse disease activity and functional status compared to those with no morbidities. CONCLUSION: Approximately 49 % of AS patients in the PSOAS cohort had multimorbidity and five distinct multimorbidity phenotypes were identified. In addition to the number of morbidities, the type of morbidity appears to be important to longitudinal outcomes in AS. The depression cluster was associated with worse disease activity and function.
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Espondilite Anquilosante , Humanos , Feminino , Masculino , Espondilite Anquilosante/epidemiologia , Estudos Prospectivos , Multimorbidade , Comorbidade , Índice de Gravidade de Doença , FenótipoRESUMO
OBJECTIVE: Sacroiliac (SI) joint and spinal inflammation are characteristic of ankylosing spondylitis (AS), but some patients with AS have been identified who have discordant radiographic disease. We studied an AS subgroup with long-standing disease and fused SI joints. We identified factors associated with discrepant degrees of radiographic damage between the SI joints and spine. METHODS: From the Prospective Study of Outcomes in AS (PSOAS) cohort, patients with a disease duration ≥ 20 years and fused SI joints were included in a nested case-control design. Patients with and without syndesmophytes were used as cases and controls for analysis. We used classification and regression tree (CART) analysis to determine risk factors for syndesmophytes presence and reexamined the validity of the risk factors using univariable logistic regression models. RESULTS: There were 354 patients in the subgroup, 23 of whom lacked syndesmophytes. CART analysis showed females were less likely to have syndesmophytes. The next important predictor was age of symptom onset in males, with age of onset ≤ 16 years being less likely to have syndesmophytes. Univariable analysis confirmed females were less likely to have syndesmophytes (odds ratio [OR] 0.17, 95% CI 0.07-0.41). Syndesmophyte presence was associated with HLA-B27 positivity (P = 0.03) and age of symptom onset > 16 years old (OR 2.72, 95% CI 1.15-6.45). All 23 patients who lacked syndesmophytes were HLA-B27 positive. CONCLUSION: Using CART analysis and univariable modeling, women were less likely to have syndesmophytes despite advanced disease duration and SI joint disease. Patients with younger age of symptom onset were less likely to have syndesmophytes. All patients without syndesmophytes were HLA-B27 positive, indicating HLA-B27 positivity may be more associated with SI disease than spinal disease.
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Espondiloartropatias , Espondilite Anquilosante , Masculino , Humanos , Feminino , Adolescente , Espondilite Anquilosante/diagnóstico por imagem , Estudos Prospectivos , Antígeno HLA-B27 , Estudos de Casos e Controles , RadiografiaRESUMO
OBJECTIVE: The study objective was to explore differences in ankylosing spondylitis (AS) diagnosis experiences between men and women by examining the coding of health events over the 2 years preceding AS diagnosis. METHODS: Claims data (January 2006-April 2019) from the MarketScan databases were examined. Patients who had received two or more AS diagnoses at least 30 days apart and had at least 2 years of insurance enrollment before their first AS diagnosis were analyzed. Men were matched 1:1 to women by age, diagnosis date, insurance type, and enrollment duration. Health events (diagnosis and provider codes) were examined over 2 years before AS diagnosis and stratified by gender. Data were analyzed using univariate χ2 tests. RESULTS: Among 7744 patients, 274 of 1906 AS-related codes showed statistically significant differences between men and women. Women received more diagnosis codes than men across diagnoses and providers; the largest difference in diagnosis codes among women versus men was in peripheral symptom coding (57.7% vs. 43.9%, respectively). More women than men received diagnosis codes for depression (21.2% vs. 9.8%) and other musculoskeletal symptoms (52.8% vs. 40.0%); only gout was more common in men (6.5%) than in women (2.2%). Among men, backache codes gradually increased 12 months before AS diagnosis, whereas axial and sacroiliitis coding increased sharply immediately before diagnosis. The greatest difference in physician types visited was for rheumatologists: 64.2% of women had visits compared with 45.1% of men. CONCLUSION: Further investigation into the dissimilarities in diagnostic experiences between men and women is needed to determine whether differences are due to disease phenotype or potential cognitive bias influencing diagnostic decision-making.
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OBJECTIVES: Little is known with certainty about the natural history of spinal disease progression in ankylosing spondylitis (AS). Our objective was to discover if there were distinct patterns of change in vertebral involvement over time and to study associated clinical factors. METHODS: Data were analysed from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) observational cohort. All patients met modified New York Criteria for AS and had ≥2 sets of radiographs scored by modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) by two independent readers between 2002 and 2017. Group-based trajectory modelling (GBTM) was used to classify patients into distinct groups of longitudinal mSASSS considering sociodemographic and clinical covariables. The optimal trajectory model and number of trajectories was selected using Nagin's Bayesian information criterion (BIC). RESULTS: A total of 561 patients with 1618 radiographs were analysed. The optimum number of trajectory groups identified was four (BIC -4062). These groups were subsequently categorized as: non-progressors (204 patients), late-progressors (147 patients), early-progressors (107 patients) and rapid-progressors (103 patients). Baseline predictors associated with higher spinal disease burden groups included: baseline mSASSS, male gender, longer disease duration, elevated CRP and smoking history. In addition, time-varying anti-TNF use per year was associated with decreased mSASSS progression only in the rapid-progressor group. CONCLUSIONS: GBTM identified four distinct patterns of spinal disease progression in the PSOAS cohort. Male gender, longer disease duration, elevated CRP and smoking were associated with higher spinal disease groups. Independent confirmation in other AS cohorts is needed to confirm these radiographic patterns.
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Espondilite Anquilosante , Teorema de Bayes , Progressão da Doença , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , Coluna Vertebral/diagnóstico por imagem , Espondilite Anquilosante/diagnóstico por imagem , Inibidores do Fator de Necrose TumoralRESUMO
OBJECTIVE: We sought to explore the relationship between changes in repeated mobility measures and spinal structural progression in patients with ankylosing spondylitis (AS) over time. METHODS: We studied patients with AS from the PSOAS (Prospective Study of Outcomes in AS) cohort and performed longitudinal multivariable regression modeling to assess the relationship of structural damage measured by their regional (cervical or lumbar) modified Stoke AS Spinal Score(mSASSS) and selected cervical (eg, cervical rotation, lateral bending, and occiput-to-wall distance) and lumbar spinal mobility measures (eg, Schöber's test and lumbar lateral bending) that were collected at least every 2 years from 2003 to 2019. RESULTS: The median length of follow-up for our 518 patients with cervical mSASSS measurements and 573 with lumbar mSASSS measurements was 4.08 (interquartile range [IQR] 2.25-6.67) and 4.17 (IQR 2.25-6.67) years, respectively. Among the mobility measures, based on multivariable regression models adjusting for clinical/demographic variables and C-reactive protein, we did not observe meaningful associations between changes in spinal mobility with their respective regional mSASSS. Baseline mSASSS, male sex, increased C-reactive protein (CRP), and longer disease duration were associated with increased longitudinal mSASSS in all analyses. CONCLUSION: Our study shows that 2-year changes in individual spinal mobility measures are not reliably associated with increased, longitudinal, AS-related spinal structural progression. We also confirmed the relationship of baseline mSASSS, sex, CRP, and disease duration with AS-related structural spinal progression over time.
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Radiographic axial spondyloarthritis (also known as ankylosing spondylitis [AS]) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and entheses. It is estimated that 1 in every 200 people are affected by AS, making it an important healthcare and socioeconomic issue. In this review, we aim to explore the current understanding of AS risk factors and provide a comprehensive update. Multiple search strings were used to identify articles of interest published in PubMed between January 1, 2013, and February 1, 2021. On the basis of the literature review and analysis, we present up-to-date information on the risk factors of developing AS and our viewpoints on disease onset and progression. Multiple genetic and nongenetic risk factors have been suggested in the onset of AS. HLA-B27 is known to have a strong association with the disease, but other genes have been implicated in disease development. Aside from genetics, other factors are thought to be involved; up to 70% of patients with AS have subclinical intestinal inflammation, suggesting that the origin of the disease may be in the gut. The exact mechanism by which AS onset begins is most likely complex and multifactorial. Key Points ⢠It remains unclear how interactions between genes, microbes, mechanical stress, gender, and other environmental and lifestyle factors predispose patients to the development of ankylosing spondylitis (AS). ⢠The exact mechanisms of AS are complex and multifactorial which will require much future research ⢠Recognizing the risk factors, as well as understanding gene-environment interactions, may offer valuable insights into the etiology of AS and have important implications for diagnosis and treatment strategies.
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Espondilartrite , Espondilite Anquilosante , Antígeno HLA-B27/genética , Humanos , Inflamação , Fatores de Risco , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/genéticaRESUMO
PURPOSE: To evaluate the psychometric performance of the Ankylosing Spondylitis Quality of Life (ASQoL) scale in patients with non-radiographic axial spondyloarthritis (nr-axSpA) to assess its appropriateness as an outcome measure in future clinical studies. METHODS: Patients with active axSpA from a Phase III, randomized, double-blind, placebo-controlled trial (RAPID-axSpA, NCT01087762) were included (N = 325). Modified New York (mNY) classification criteria were used to classify patients as having ankylosing spondylitis or nr-axSpA; those with nr-axSpA were further categorized based on objective signs of inflammation. Psychometric properties of the ASQoL were assessed/documented using a mixture of modern psychometric methods and classical test theory methods. These included exploratory factor analysis and item response theory models to assess the domain structure, test the utility of a single domain relative to subdomains, assess bias, and generate statistics to guide an empirical scoring algorithm. The reliability and validity of scores were evaluated via internal consistency, test-retest reliability, concurrent validity, and known-groups validity. Score responsiveness was assessed via anchor-based clinically meaningful change, supplemented with empirical cumulative distribution function visualizations. RESULTS: The ASQoL data were defined by four domains. However, a four-domain solution was found to be inferior to a bifactor solution in which the four domains were included within a total domain. Scoring statistics supported a unit-weighted total score. Within the nr-axSpA population with objective signs of inflammation, the ASQoL mean score had adequate reliability, validity, and ability to detect clinically meaningful change. CONCLUSIONS: Our findings suggest that the ASQoL is an appropriate outcome measure in interventional clinical trials in patients with nr-axSpA.
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Psicometria/métodos , Qualidade de Vida/psicologia , Espondilartrite/complicações , Espondilite Anquilosante/epidemiologia , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Adulto JovemRESUMO
INTRODUCTION/OBJECTIVES: The effect of intravenous (IV) golimumab on health-related quality of life (HRQoL) and productivity in patients with ankylosing spondylitis (AS) was evaluated. METHOD: Patients were randomized to IV golimumab 2 mg/kg (n = 105) at weeks 0, 4, then every 8 weeks (q8w) through week 52 or placebo (n = 103) at weeks 0, 4, 12, with crossover to golimumab 2 mg/kg at weeks 16, 20, then q8w through week 52. Changes from baseline in EuroQol-5 dimension-5 level (EQ-5D-5L) index and visual analog scale (EQ-VAS), daily productivity VAS, Work Limitations Questionnaire (WLQ), and Ankylosing Spondylitis Quality of Life (ASQoL) were assessed. Correlations between these outcomes and disease activity and patient functioning outcomes were evaluated post hoc. RESULTS: At week 16, changes from baseline (mean ± standard deviation) in EQ-5D-5L index (0.17 ± 0.16 vs 0.05 ± 0.14), EQ-VAS (20.3 ± 24.6 vs 4.8 ± 23.5), daily productivity VAS (- 2.9 ± - 2.9 vs - 1.1 ± - 2.5), WLQ productivity loss score (- 3.5 ± - 5.3 vs - 1.9 ± - 4.0), and ASQoL (- 5.4 ± - 5.0 vs - 1.8 ± - 4.5) were greater in the IV golimumab versus placebo group, respectively. At week 28, changes from baseline were similar between the IV golimumab and placebo-crossover groups (EQ-5D-5L index: 0.18 ± 0.17 and 0.16 ± 0.16, EQ-VAS: 20.5 ± 27.9 and 22.5 ± 23.1, daily productivity VAS: - 3.1 ± - 3.0 and - 3.1 ± - 2.8, WLQ productivity loss: - 3.9 ± - 5.5 and - 4.5 ± - 4.5, and ASQoL: - 5.3 ± - 5.2 and - 5.3 ± - 4.8, respectively); improvements were maintained through week 52. HRQoL and productivity outcomes were generally moderately correlated with disease activity and functioning outcomes. CONCLUSIONS: In patients with AS, IV golimumab produced sustained improvements in HRQoL and productivity through 1 year, which correlated with improvements in disease activity and functioning. ClinicalTrials.gov registry number is NCT02186873. Key Points ⢠Intravenous (IV) golimumab resulted in clinically important improvement in general and ankylosing spondylitis-specific health-related quality of life (HRQoL) and productivity outcomes in patients with ankylosing spondylitis (AS) as early as week 8 and maintained improvement through 1 year ⢠Improvements in HRQoL and productivity outcomes in these patients with AS were correlated with improvements in measures of disease activity and patient functional capability ⢠IV golimumab is an effective treatment option for AS that can help mitigate the negative effects of the disease on HRQoL and productivity.
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Antirreumáticos , Espondilite Anquilosante , Adulto , Anticorpos Monoclonais , Antirreumáticos/uso terapêutico , Método Duplo-Cego , Humanos , Qualidade de Vida , Índice de Gravidade de Doença , Espondilite Anquilosante/tratamento farmacológico , Resultado do TratamentoRESUMO
PURPOSE: The ankylosing spondylitis quality of life (ASQoL) instrument is widely used to assess health-related quality of life in patients with ankylosing spondylitis (AS). We assessed the relevance of the ASQoL items in patients with non-radiographic axial spondyloarthritis (nr-axSpA), a distinct subgroup within the axSpA disease spectrum. METHODS: This observational, cross-sectional, qualitative interview study recruited patients from clinic settings. Interviews from patients with axSpA who participated in a prior qualitative study were also used. Patients initially underwent a concept elicitation interview using open-ended questions to evaluate relevance of the concepts measured by the ASQoL. They then completed the ASQoL and underwent a cognitive interview to assess their understanding of the items, instructions and response options. Transcripts from patients who participated in the previous qualitative study (who did not complete the ASQoL or undergo cognitive interview) were evaluated to identify expressions of the concepts in the ASQoL. RESULTS: A total of 18 patients with nr-axSpA participated. The concept elicitation interview findings supported the relevance of the ASQoL items. Cognitive interviews determined that the ASQoL was easily understood; the 13 new patients chose a response for each item that matched their experience with nr-axSpA. Transcripts for the five previously interviewed patients confirmed the concepts presented in the ASQoL items were relevant and important to their experience of living with nr-axSpA. CONCLUSIONS: Our results represent an important first step in confirming the relevance of the concepts in the ASQoL to patients with nr-axSpA, supporting quantitative assessment of ASQoL validity in this population.
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Qualidade de Vida/psicologia , Espondilite Anquilosante/psicologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.
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Produtos Biológicos , Espondilite Anquilosante , Produtos Biológicos/uso terapêutico , Humanos , Estudos Prospectivos , Índice de Gravidade de Doença , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/epidemiologia , Fator de Necrose Tumoral alfaRESUMO
OBJECTIVES: Although cross-sectional studies have shown that ankylosing spondylitis-specific factors correlate with depressive symptom severity, the association of these factors over time is unresolved. We examined the demographic and clinical factors associated with longitudinal depressive symptom severity in AS patients. METHODS: We analyzed sociodemographic, clinical, behavioral and medication data from 991 patients from the Prospective Study of Outcomes in Ankylosing spondylitis cohort, and measured depression severity with the Center for Epidemiological Studies Depression (CES-D) Scale administered at approximately 6-month visit intervals. Multivariable longitudinal negative binomial regression models were conducted using generalized estimating equation modeling to assess the demographic, clinical, and medication-related factors associated with depression severity by CES-D scores over time. RESULTS: The median baseline CES-D score (possible range 0-60) was 10.0 (interquartile range = 5, 17). In longitudinal multivariable analyses, higher CES-D scores were associated with longitudinal smoking, greater functional impairment, greater disease activity, self-reported depression, and poor global health scores. Marital status (e.g., being married) was associated with lower CES-D. Adjusted mean CES-D scores in our model decreased over time, with a significant interaction between time and gender observed. CONCLUSION: This study identified longitudinal clinical factors such as greater disease activity, greater functional impairment, and poor global health to be associated with longitudinal depression severity. These factors are potentially modifiable and may help manage depressive symptoms in AS.
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Depressão/psicologia , Espondilite Anquilosante/psicologia , Atividades Cotidianas , Adulto , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antidepressivos/uso terapêutico , Estudos de Coortes , Depressão/tratamento farmacológico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/uso terapêutico , Índice de Gravidade de Doença , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/fisiopatologia , Inibidores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
OBJECTIVE: To assess the reliability and validity in ankylosing spondylitis (AS) of selected Patient Reported Outcomes Measurement Information System (PROMIS) Short Forms (SF) developed by the US National Institutes of Health. The analysis was done across core sets and patient-identified domains of the Assessment of Spondyloarthritis international Society. METHODS: Participants in the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS), an ongoing, prospective longitudinal observational study, completed 6 PROMIS SF assessing global health, depression, fatigue, physical function, pain intensity, and pain interference during their PSOAS visits from September 2017 to January 2019. Test-retest reliability and internal consistency were assessed using intraclass correlation coefficients and Cronbach's alpha coefficient, respectively. PROMIS SF were compared to legacy measures collected. Construct validity was evaluated through examination of score distributions and floor effects, and through examination of the Spearman correlation coefficients between PROMIS measures and existing legacy AS measures. Discriminant validity was tested across Ankylosing Spondylitis Disease Activity Score (ASDAS) groups. RESULTS: Participants (n = 119) were mostly male (69%), white (81%), and with a mean (SD) age of 51 (± 15) years. Legacy measures demonstrated floor effects that were not present in PROMIS SF. Good test-retest reliability (r > 0.8) and excellent internal consistency (α > 0.9) was noted in the PROMIS SF. The 6 PROMIS SF correlated moderately to strongly [ρ 0.68 (Depression) to -0.87 (Physical Function)] with appropriate legacy measures. PROMIS scores measures worsened significantly (p < 0.05) with higher ASDAS groups. CONCLUSION: This study supports the reliability and construct validity of PROMIS SF to assess AS symptoms from a single-center sample of patients with AS. Further research is needed to test responsiveness, feasibility/resource burden, and different cultural/societal contexts for patients with AS.
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Espondilite Anquilosante , Adulto , Idoso , Feminino , Humanos , Sistemas de Informação , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Qualidade de Vida , Reprodutibilidade dos Testes , Espondilite Anquilosante/diagnóstico , Inquéritos e QuestionáriosRESUMO
Decreased clearance is the main reason amyloid-beta protein (Abeta) is increased in the brains of patients with Alzheimer's disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Abeta at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Abeta42, increased brain levels of Abeta42, and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Abeta could increase and AD would be promoted.