RESUMEN
OBJECTIVE: To identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS). METHODS: Cohorts of male and female patients with AS and age- and sex-matched healthy control subjects were selected, and the levels of serum cytokines (interferon-γ [IFNγ], tumor necrosis factor α, interleukin-17A [IL-17A], and IL-6) were examined by enzyme-linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches. RESULTS: The frequency of IL-17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS-associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex-related immune profiles were independent of HLA-B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS. CONCLUSION: The results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex-related differences in the clinical features of AS and could provide a rationale for sex-specific treatment of AS.
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Espondilitis Anquilosante/inmunología , Células Th17/patología , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Expresión Génica , Humanos , Interferón gamma/sangre , Interleucina-17/sangre , Masculino , Análisis por Micromatrices , Fragmentos de Péptidos/sangre , Reacción en Cadena de la Polimerasa , Transcripción Reversa , Factores Sexuales , Espondilitis Anquilosante/sangre , Células TH1/patología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
OBJECTIVE: In this study, we aimed to address the prevalence of fatigue, its associated factors, and the effect of tumor necrosis factor inhibitors (TNFi) on this subgroup of patients in a large axial spondyloarthritis (axSpA) cohort. METHODS: The study included 681 patients [ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA)]. The Fatigue Severity Scale (FSS) and the Bath AS Disease Activity Index question 1 (BASDAI Q1) indices were used for fatigue assessment. Severe fatigue was defined as an FSS ≥ 4 or a BASDAI Q1 ≥ 5. Disease activity, function, and quality of life (QoL) measures were recorded. Patients who had been treated with TNFi were identified, and baseline and followup data were analyzed. RESULTS: Of the cohort, 67.3% had severe fatigue, and the prevalence was similar between AS (67.2%) and nr-axSpA (68.2%). Severely fatigued patients tended to have higher disease activity scores, increased acute-phase proteins, and decreased QoL measures. TNFi therapy was associated with improvement in disease activity, and although this treatment led to significantly decreased fatigue scores, this reduction was not optimal in the majority of patients with 80% continuing to have severe fatigue according to their posttreatment scores. Health Assessment Questionnaire, mean scores of BASDAI Q5 and Q6, and BASDAI enthesitis were independent predictors of fatigue severity. CONCLUSION: Fatigue is a common symptom in axSpA, and the burden of fatigue among patients with nr-axSpA is similar to that seen in AS. While biologics are effective in improving disease activity, their effect on fatigue is more limited. In axSpA, fatigue remains unresponsive to TNFi in nearly 80% of patients.
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Fatiga/epidemiología , Espondiloartritis/epidemiología , Espondilitis Anquilosante/diagnóstico por imagen , Espondilitis Anquilosante/epidemiología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Distribución por Edad , Estudios de Cohortes , Comorbilidad , Fatiga/tratamiento farmacológico , Fatiga/fisiopatología , Femenino , Humanos , Incidencia , Funciones de Verosimilitud , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Radiografía , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Espondiloartritis/tratamiento farmacológico , Espondiloartritis/fisiopatología , Espondilitis Anquilosante/tratamiento farmacológico , Espondilitis Anquilosante/fisiopatología , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/efectos de los fármacosRESUMEN
OBJECTIVES: Clinical research data are often collected on paper and later inputted onto an electronic database. This method is time consuming and potentially introduces errors. Therefore, to make primary data collection more efficient and less error prone we aimed to develop a touch-screen application for data collection in a psoriatic arthritis research clinic and compared it with the pre-existing paper-based system. METHODS: We developed a Web application using Java and optimized it for the iPad®. It highlights missing fields for physicians in real time, and only permits submission of data collection form after corrections are made. For its evaluation, seven physicians participated, and before each patient visit they were randomly assigned paper or iPad® data entry. Number of errors, length of visit, and time between clinic visit and completion of data entry were measured. RESULTS: A total of 106 patients seen in the clinic who agreed to participate were randomly assigned to be evaluated by clinic physicians using the iPad® (fifty-three patients) or a paper protocol (fifty-three patients). On average, 3.34 omissions were found per paper form, of which 2.24 would have been detected on the iPad®. The iPad® increased the mean patient encounter time from 37.2 minutes to 46.5 minutes, but eliminated delay between a clinic visit and its data entry. CONCLUSIONS: Entering data using the iPad® application makes the patient encounter slightly longer, but reduces "missing fields." It also eliminates the delay between clinic visit and data entry thus improving the efficiency of clinical data capture in a research setting.
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Investigación Biomédica/métodos , Computadoras de Mano , Recolección de Datos/métodos , Internet , Reumatología , Humanos , Factores de Tiempo , Interfaz Usuario-ComputadorRESUMEN
OBJECTIVES: Long-term data on infection risk in axial SpA (axSpA) are sparse. TNF inhibitors (TNFis) are increasingly being used in axSpA, with infection being the most important adverse event. We aimed to investigate the frequency of infections in axSpA and to identify factors predisposing to infection. METHODS: Data were extracted from a longitudinal observational cohort of patients with axSpA. Infection rates were calculated and multivariate analysis was performed to investigate the association of independent variables with infection. RESULTS: Data were analysed for 440 patients followed for a total of 1712 patient-years (pys). A total of 259 infections, of which 23 were serious, were recorded in 185 patients. The overall rate of any infection was 15 (95% CI 13, 17)/100 pys and the serious infection rate was 1.3 (95% CI 0.9, 2.0)/100 pys. There was no significant difference in the rate of any infection or serious infection in patients on TNFis compared with patients never on biologic agents. In the multivariate analysis, DMARD treatment, but not TNFi treatment, was associated with risk of infection. Age, disease duration, smoking status, BASFI, BASDAI, co-morbidity score and hospitalization were not associated with an increased risk of infection. CONCLUSION: The serious infection rate in axSpA in this observational cohort is low when compared with rates reported in other rheumatic diseases. Biologic use was not a significant risk factor for serious infection.
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Antirreumáticos/uso terapéutico , Vértebra Cervical Axis , Infecciones/epidemiología , Espondiloartritis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Estudios de Cohortes , Femenino , Glucocorticoides/uso terapéutico , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de RiesgoRESUMEN
OBJECTIVE: (1) To determine the prevalence of depression and anxiety in patients with psoriatic arthritis (PsA) and to identify associated demographic and disease-related factors. (2) To determine whether there is a difference in the prevalence of depression and anxiety between patients with PsA and those with psoriasis without PsA (PsC). METHODS: Consecutive patients attending PsA and dermatology clinics were assessed for depression and anxiety using the Hospital Anxiety and Depression Scale. Patients underwent a clinical assessment according to a standard protocol and completed questionnaires assessing their health and quality of life. T tests, ANOVA, and univariate and multivariate models were used to compare depression and anxiety prevalence between patient cohorts and to determine factors associated with depression and anxiety. RESULTS: We assessed 306 patients with PsA and 135 with PsC. There were significantly more men in the PsA group (61.4% vs 48% with PsC) and they were more likely to be unemployed. The prevalence of both anxiety and depression was higher in patients with PsA (36.6% and 22.2%, respectively) compared to those with PsC (24.4% and 9.6%; p = 0.012, 0.002). Depression and/or anxiety were associated with unemployment, female sex, and higher actively inflamed joint count as well as disability, pain, and fatigue. In the multivariate reduced model, employment was protective for depression (OR 0.36) and a 1-unit increase on the fatigue severity scale was associated with an increased risk of depression (OR 1.5). CONCLUSION: The rate of depression and anxiety is significantly higher in patients with PsA than in those with PsC. Depression and anxiety are associated with disease-related factors.
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Trastornos de Ansiedad/epidemiología , Artritis Psoriásica/epidemiología , Artritis Psoriásica/psicología , Trastorno Depresivo/epidemiología , Actividades Cotidianas , Adulto , Anciano , Trastornos de Ansiedad/diagnóstico , Trastorno Depresivo/diagnóstico , Evaluación de la Discapacidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Prevalencia , Psoriasis/epidemiología , Psoriasis/psicología , Calidad de Vida , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
OBJECTIVES: We conducted a case-control study to determine the association between KIR2D and KIR3D gene polymorphisms and their interaction with HLA alleles in PsA. METHODS: A total of 678 subjects with PsA and 688 healthy controls were studied. Differences between cases and controls in the frequency of individual KIR polymorphisms were tested for significance by an asymptotic χ(2) test and Fisher's exact test. Trends for increasing susceptibility to PsA from combined genotypes (HLA-KIR and HLA) were evaluated by the Cochran-Armitage trend test. Multigene logistic regression analysis was conducted to identify independent associations and interactions. RESULTS: In univariate analyses, KIR2DL2 and KIR2DS2 polymorphisms were significantly associated with PsA. Only KIR2DS2 was associated with PsA compared with healthy controls in multivariate analysis [odds ratio (OR) 1.25, 95% CI 1.01, 1.54, P = 0.044]. The presence of HLA-C group 2 alleles was associated with a higher risk of PsA (trend test P = 0.006). The risk of PsA is higher when KIR2DS2 is present with the HLA-C ligands (C group 1) for the corresponding inhibitory KIRs, and is highest when KIR2DS2 is present in the absence of HLA-C ligands for homologous inhibitor KIRs, compared with the state when KIR2DS2 is absent (trend test P = 0.027). The presence of HLA-C alleles that have high cell surface expression was also associated with a higher risk of PsA (trend test P < 0.001). HLA-B Bw4 and HLA-B Bw4 80ile allele groups were associated with a higher PsA risk (trend test P < 0.0001 for both analyses). CONCLUSION: This study confirms the association of the KIR2DS gene, especially KIR2DS2, with PsA.
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Artritis Psoriásica/genética , Receptores KIR2DL2/genética , Receptores KIR/genética , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Antígenos HLA-C/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo Genético , Análisis de RegresiónRESUMEN
OBJECTIVE: To investigate the features of ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA) in a Canadian cohort of 639 patients with AS and 73 patients with nr-axSpA. METHODS: Clinical and laboratory data were compared for patients with AS and nr-axSpA enrolled in a longitudinal SpA cohort. RESULTS: The proportion of male patients was higher in AS than in nr-axSpA (76.2% vs 47.9%; p < 0.0001). There was no difference in the presence of HLA-B27 between AS (78.9%) and nr-axSpA (72.5%) patients, nor in age at the time of diagnosis, although AS patients were younger at the time of symptom onset (23.9 yrs vs 26.4 yrs; p = 0.03). Disease duration at the time of last clinic visit was longer for AS than for nr-axSpA patients (17.7 yrs vs 12.1 yrs; p = 0.0002). Acute-phase reactants were higher in AS than in nr-axSpA (C-reactive protein 11.4 vs 5.2, p < 0.0001; erythrocyte sedimentation rate 13.7 vs 9.9, p = 0.02). The Bath Ankylosing Spondylitis Metrology Index was higher in patients with AS (2.84 vs 1.35, p < 0.0001). CONCLUSION: Patients with nr-axSpA were more likely to be female and to have lower inflammatory markers than patients with AS. When restricted to female patients only, acute-phase reactants did not differ significantly between AS and nr-axSpA. The evidence provides indirect support for the concept that nr-axSpA may represent an early form of AS, but that also has features of a distinct disease entity with significant burden of symptoms.
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Espondiloartritis/clasificación , Espondiloartritis/diagnóstico , Espondilitis Anquilosante/clasificación , Espondilitis Anquilosante/diagnóstico , Reacción de Fase Aguda/metabolismo , Adolescente , Adulto , Edad de Inicio , Biomarcadores/metabolismo , Proteína C-Reactiva/metabolismo , Canadá , Estudios de Cohortes , Femenino , Antígeno HLA-B27/metabolismo , Humanos , Estudios Longitudinales , Masculino , Estudios Prospectivos , Espondiloartritis/inmunología , Espondilitis Anquilosante/inmunología , Adulto JovenRESUMEN
OBJECTIVE: Our purpose was to determine associations between HLA alleles and psoriatic arthritis (PsA). METHODS: 678 PsA cases and 688 healthy controls were analyzed in a case-control design. The difference in the proportion of cases and controls with at least 1 copy of HLA alleles were tested for significance using χ(2) test and Fisher's exact test. Association analyses of haplotypes inferred by the Expectation-Maximization algorithm were performed. In the family-based association study, data from 283 families were analyzed. RESULTS: Univariate analysis revealed that cases were more likely to be carriers of HLA-C*01, -C*02, -C*06, -C*12, -B*27, -B*38 and -B*57, whereas controls were more likely to be carriers of HLA-C*03, -C*07, -B*07, -B*51, -DRB1*15 and -DQB1*0602. In haplotype analyses, PsA cases were more likely to be carriers of the HLA haplotypes -C*01/-B*27, -C*02/-B*27, -C*12/-B*38, and -C*06/-B*57, while controls were more likely to be carriers of the haplotypes -C*07/-B*07 and -C*15/-B*51. In the family-based association analysis, the HLA alleles -A*02, -B*27 and -DRB1*07 were preferentially transmitted to cases, whereas the alleles -A*03, -A*28, -B*51, -DRB1*11 and -DQB1*0301 were under transmitted. CONCLUSION: This large case-control and family based association study shows that HLA-C*12/B*38, HLA-B*27 and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA. However, since patients with PsA also have psoriasis it is difficult to determine whether the primary association is with arthritis or psoriasis.
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Alelos , Artritis Psoriásica/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Haplotipos , Prueba de Histocompatibilidad , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Adulto JovenRESUMEN
The Spondyloarthritis Research Consortium of Cananda (SPARCC) is a transdiscliplinary research network of investigators interested in spondyloarthritis. The group has been supported by a new research initiative by The Arthritis Society. SPARCC aims to address the genetic basis of susceptibility of the disease and develop and validate clinical and imaging outcomes to assess disease activity and structural damage over time, the response to therapy, and the clinical burden of illness in terms of quality of life and disability. The first step was to develop a database that would allow ascertainment of phenotype for genetic studies, as well as accurate and detailed longitudinal information for disease expression and outcome studies. This article describes the SPARCC database and outlines difficulties and possible solutions for maintaining such a database.
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Bases de Datos como Asunto , Sistema de Registros , Espondiloartritis , Adulto , Biomarcadores/sangre , Canadá , Citocinas/sangre , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Espondiloartritis/genética , Espondiloartritis/patología , Espondiloartritis/terapiaRESUMEN
Efficient freezing, archiving, and thawing of sperm are essential techniques to support large scale research programs using mouse models of human disease. The purpose of this study was to investigate the effects of variable combinations and concentrations of cryoprotectants on sperm-assessment parameters of frozen-thawed mouse sperm in order to optimize cryopreservation protocols. Sperm was frozen using combinations of 3% skim milk + 0.2 or 0.3 M nonpermeating raffinose with either permeating glucose, fructose, propylene glycol, ethylene glycol, glycerol, or sodium pyruvate in CD-1, C3FeB6F1/J, B6129SF1, C57BL/6NCrIBR, 129S/SvPaslco, and DBA/2NCrIBR mice. Sperm-assessment parameters included progressive motility, plasma membrane integrity (SYBR-14 + PI), in vitro fertilization rate, and in vitro embryo development rate to blastocyst. DNA content analysis of sperm was measured by the sperm chromatin structure assay (SCSA). 0.3 M raffinose with 0.1 M fructose significantly improved post-thaw sperm-assessment parameters for CD-1, C3B6F1, B6129SF1 mice (P < 0.05-0.01), whereas 0.2 M raffinose with 0.1 M glycerol or 0.1 M fructose enhanced sperm assessment values for C57BL/6 and 129S mice (P < 0.01), compared to 0.3 M raffinose alone. DNA fragmentation during cryopreservation was significantly increased in all strains evaluated when compared with fresh control sperm in a strain-dependent manner (P < 0.01). Supplementation with permeating glycerol or fructose to the cryoprotectant (CPA) solution showed a significant protective effect to DNA integrity when cryopreserving sperm from C57BL/6 and 129S mice. Damage to sperm DNA significantly decreased the rate of in vitro embryo development to blastocyst in C57BL/6 mice. The type of monosaccharide sugar or polyols, CPA molarity, and combination of permeating and nonpermeating cryoprotectant are significant factors for improving progressive motility, plasma membrane integrity, DNA integrity, in vitro fertilization rate, and in vitro embryo development rate to blastocyst in cryopreserved mouse sperm.