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1.
Ir J Med Sci ; 193(1): 443-448, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37418106

RESUMO

BACKGROUND: Axial spondyloarthritis (axSpA) comprises patients with both radiographic and non-radiographic features. Previous studies have shown similar burden of disease between these two groups. AIMS: The Ankylosing Spondylitis Registry of Ireland (ASRI) was formed with the objective to measure the burden of axial spondyloarthritis in the population and identify early predictors of a poor outcome. For this analysis, the ASRI database was used to compare the characteristics and burden of disease in patients with radiographic versus non-radiographic axial spondyloarthritis. METHODS: Patients with radiographic axial spondyloarthritis (r-axSpA) were defined as those with X-ray evidence of sacroiliitis. Patients with non-radiographic axial spondyloarthritis (nr-axSpA) were defined as having MRI evidence of sacroiliitis but no X-ray evidence of sacroiliitis. RESULTS: In total, 764 patients were included. Analysis of radiographic status showed 88.1% (n = 673) of patients with r-axSpA and 11.9% (n = 91) with nr-axSpA (Table 1). Patients with nr-axSpA were younger (41.3 vs. 46.6 years, p < 0.01), had shorter disease duration (14.8 vs. 20.2 years, p < 0.01) and had lower proportion of males (66.6% vs. 78.4%, p = 0.02) with lower frequency of HLA-B27 positivity (73.6% vs. 90.5%, p < 0.01). The nr-axSpA group had lower BASDAI (3.37 vs. 4.05, p = 0.01), BASFI (2.46 vs. 3.88, p < 0.01), BASMI (2.33 vs. 4.34, p < 0.01), ASQoL (5.2 vs. 6.67, p = 0.02) and HAQ scores (0.38 vs. 0.57, p < 0.01). There were no significant differences in the prevalence of extra-musculoskeletal manifestations or use of medications. CONCLUSIONS: This study provides evidence to suggest that the burden of disease is less in patients with non-radiographic axial spondyloarthritis than radiographic axial spondyloarthritis.


Assuntos
Espondiloartrite Axial não Radiográfica , Sacroileíte , Espondilartrite , Espondilite Anquilosante , Masculino , Humanos , Espondilite Anquilosante/tratamento farmacológico , Espondilartrite/tratamento farmacológico , Espondilartrite/epidemiologia , Irlanda , Sistema de Registros , Efeitos Psicossociais da Doença
2.
Blood ; 142(3): 290-305, 2023 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-37192286

RESUMO

Despite >80 years of clinical experience with coagulation factor VIII (FVIII) inhibitors, surprisingly little is known about the in vivo mechanism of this most serious complication of replacement therapy for hemophilia A. These neutralizing antidrug alloantibodies arise in ∼30% of patients. Inhibitor formation is T-cell dependent, but events leading up to helper T-cell activation have been elusive because of, in part, the complex anatomy and cellular makeup of the spleen. Here, we show that FVIII antigen presentation to CD4+ T cells critically depends on a select set of several anatomically distinct antigen-presenting cells, whereby marginal zone B cells and marginal zone and marginal metallophilic macrophages but not red pulp macrophages (RPMFs) participate in shuttling FVIII to the white pulp in which conventional dendritic cells (DCs) prime helper T cells, which then differentiate into follicular helper T (Tfh) cells. Toll-like receptor 9 stimulation accelerated Tfh cell responses and germinal center and inhibitor formation, whereas systemic administration of FVIII alone in hemophilia A mice increased frequencies of monocyte-derived and plasmacytoid DCs. Moreover, FVIII enhanced T-cell proliferation to another protein antigen (ovalbumin), and inflammatory signaling-deficient mice were less likely to develop inhibitors, indicating that FVIII may have intrinsic immunostimulatory properties. Ovalbumin, which, unlike FVIII, is absorbed into the RPMF compartment, fails to elicit T-cell proliferative and antibody responses when administered at the same dose as FVIII. Altogether, we propose that an antigen trafficking pattern that results in efficient in vivo delivery to DCs and inflammatory signaling, shape the immunogenicity of FVIII.


Assuntos
Linfócitos T CD4-Positivos , Fator VIII , Hemofilia A , Hemostáticos , Animais , Camundongos , Células Dendríticas/metabolismo , Fator VIII/imunologia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemostáticos/imunologia , Hemostáticos/uso terapêutico , Ovalbumina/imunologia
3.
Trials ; 23(1): 743, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064592

RESUMO

BACKGROUND: Axial involvement constitutes a specific domain of psoriatic arthritis (PsA). Interleukin (IL)-23 inhibitors have demonstrated improvement in axial PsA (axPsA) symptoms, but have not shown efficacy in treating ankylosing spondylitis (AS), suggesting differences in axPsA processes and treatments. In a post hoc, pooled analysis of patients with investigator- and imaging-confirmed sacroiliitis in two phase 3, randomized, placebo-controlled studies (DISCOVER-1 and DISCOVER-2), patients treated with guselkumab, an IL-23p19 inhibitor, had greater axial symptom improvements compared with placebo. Confirmatory imaging at baseline was restricted to the sacroiliac (SI) joints, occurred prior to/at screening, and was locally read. METHODS: The STAR study will prospectively assess efficacy outcomes in PsA patients with magnetic resonance imaging (MRI)-confirmed axial inflammation. Eligible, biologic-naïve patients with PsA (N =  405) for ≥ 6 months and active disease (≥ 3 swollen and ≥ 3 tender joints, C-reactive protein [CRP] ≥ 0.3 mg/dL) despite prior non-biologic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs will be randomized (1:1:1) to guselkumab every 4 weeks (Q4W); guselkumab at week (W) 0, W4, then every 8 weeks (Q8W); or placebo with crossover to guselkumab at W24, W28, then Q8W. Patients will have Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4, spinal pain component score (0-10 visual analog scale) ≥ 4, and screening MRI-confirmed axial involvement (positive spine and/or SI joints according to centrally read Spondyloarthritis Research Consortium of Canada [SPARCC] score ≥ 3 in ≥ 1 region). The primary endpoint is mean change from baseline in BASDAI at W24; multiplicity controlled secondary endpoints at W24 include AS Disease Activity Score employing CRP (ASDAS), Disease Activity Index for PsA (DAPSA), Health Assessment Questionnaire - Disability Index (HAQ-DI), Investigator's Global Assessment of skin disease (IGA), and mean changes from baseline in MRI SI joint SPARCC scores. Centrally read MRIs of spine and SI joints (scored using SPARCC) will be obtained at W0, W24, and W52, with readers blinded to treatment group and timepoint. Treatment group comparisons will be performed using a Cochran-Mantel-Haenszel or chi-square test for binary endpoints and analysis of covariance, mixed model for repeated measures, or constrained longitudinal data analysis for continuous endpoints. DISCUSSION: This study will evaluate the ability of guselkumab to reduce both axial symptoms and inflammation in patients with active PsA. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, NCT04929210 , on 18 June 2021. PROTOCOL VERSION: Version 1.0 dated 14 April 2021.


Assuntos
Artrite Psoriásica , Espondilartrite , Espondilite Anquilosante , Anticorpos Monoclonais Humanizados , Artrite Psoriásica/diagnóstico por imagem , Artrite Psoriásica/tratamento farmacológico , Proteína C-Reativa , Ensaios Clínicos Fase IV como Assunto , Método Duplo-Cego , Humanos , Inflamação , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilartrite/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Resultado do Tratamento
4.
Rheumatology (Oxford) ; 61(12): 4731-4740, 2022 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-35274691

RESUMO

OBJECTIVES: SLE significantly impairs health-related quality of life (HRQoL). In this post hoc analysis, structural equation modelling was used to examine the 'causal cascade' of interaction between anifrolumab, disease activity and patient-reported outcomes (PROs) in pooled data from the phase 3 TULIP-1 and TULIP-2 trials. METHODS: Data were pooled from the TULIP-1 (n = 364) and TULIP-2 (n = 362) randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). We evaluated changes from baseline to week 24 and week 52 in four clinical (BICLA, BILAG-2004, SLEDAI-2K and changes in glucocorticoid dosage) and six PRO measures (SF-36, FACIT-F, EQ-5D, LupusQoL, PHQ-8 and pain NRS) in our hypothesized model of interactions. RESULTS: Our hypothesized model had an acceptable fit to the pooled TULIP trial data. At week 24, significant paths revealed that when compared with placebo, anifrolumab treatment improved disease activity as measured by BICLA, BILAG-2004, SLEDAI-2K and changes to glucocorticoid dosage. In turn, these clinical measures reduced pain, which improved fatigue, physical functioning, mood/emotions and HRQoL. When the model incorporated number of glucocorticoid tapers as the measure of change in glucocorticoid dosage, treatment effects of anifrolumab on glucocorticoid tapers were not retained at week 52. However, at week 52 treatment indirectly improved HRQoL through its direct effects on BICLA. CONCLUSIONS: Anifrolumab is associated with significant patient-reported improvements in aspects of HRQoL including pain, fatigue, mood and physical function. These benefits are from the direct effect of anifrolumab treatment on disease activity and reduction in glucocorticoid dosage.


Assuntos
Lúpus Eritematoso Sistêmico , Qualidade de Vida , Humanos , Análise de Classes Latentes , Glucocorticoides/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Fadiga , Dor , Resultado do Tratamento
5.
J Asthma ; 59(9): 1859-1868, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34374622

RESUMO

OBJECTIVE: For patients with severe asthma (SA), overestimation of asthma control may lead to poorer outcomes. The objective of this study was to assess concurrent patient and specialist assessments of asthma control and treatment effectiveness among a large US cohort of SA patients. METHODS: CHRONICLE is an ongoing observational study of patients with SA treated by US subspecialists. Asthma control was assessed using the patient-completed Asthma Control Test™ (ACT™) and specialist clinical assessment of control. Treatment effectiveness was measured using the Global Evaluation of Treatment Effectiveness (GETE) completed by patients and specialists. RESULTS: 1109 patients who completed online surveys at enrollment were included. 14%, 28%, 25%, and 33% of patients had ACT™ scores of 5-9, 10-15, 16-19, and 20-25, respectively. Compared with 67% of patients with uncontrolled asthma by ACT™, 44% were uncontrolled by specialist assessment. 54% of patients who were uncontrolled according to the ACT™ were rated as controlled by specialists, demonstrating overestimation of asthma control. Based on ACT™ score, asthma control was more frequent among patients treated with biologics compared to other treatments. Using the GETE, 90% of patients reported treatment effectiveness compared with 71% of specialists. Patient and specialist treatment effectiveness categorizations agreed 73% of the time. CONCLUSION: Specialists commonly overestimated asthma control relative to ACT™ scores. Patients reported treatment effectiveness more frequently than specialists. These findings emphasize the importance of validated instruments to assess asthma control and reduce potential treatment gaps associated with patient-specialist discordance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.


Assuntos
Asma , Produtos Biológicos , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Humanos , Estudos Longitudinais , Inquéritos e Questionários , Resultado do Tratamento , Estados Unidos
6.
J Allergy Clin Immunol Pract ; 10(5): 1249-1259, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34896298

RESUMO

BACKGROUND: The Asthma Daytime Symptom Diary (ADSD) and the Asthma Nighttime Symptom Diary (ANSD) were developed to meet the need for standardized patient-reported measures of asthma symptoms to assess treatment trial outcomes in adults and adolescents. OBJECTIVE: To determine scoring and evaluate the measurement properties of the ADSD/ANSD. METHODS: Adolescents (12-17 years) and adults (18+ years) with asthma completed draft 8-item electronic versions of the ADSD/ANSD for 10 days alongside the Adult Asthma Symptom Daily Scales (AASDS) and a Patient Global Impression of Severity (PGIS). Using classical and modern psychometric methods, initial analyses evaluated the performance of ADSD/ANSD items to inform scoring. Subsequent analyses evaluated the reliability and validity of ADSD/ANSD scores. RESULTS: A demographically and clinically diverse sample (n = 130 adolescents; n = 89 adults) was recruited. Item performance was generally strong. However, items assessing chest pressure and mucus/phlegm demonstrated redundancy and poorer performance and were removed. Principal-components analysis, confirmatory factor analysis, and item response theory supported combining items to form 6-item total ADSD/ANSD scores. Internal consistency (α = 0.94-0.95) and test-retest reliability (intraclass correlation coefficient = 0.86-0.95) were strong. Strong correlations (r = 0.72-0.80) were observed between ADSD scores and AASDS items assessing asthma symptom frequency, bother, and impact on activities. Significant differences (P < .001) in mean ADSD/ANSD scores were observed between groups categorized by asthma severity (PGIS), asthma control, inhaler use, nebulizer use, activity limitations, and nighttime awakenings. CONCLUSIONS: The ADSD/ANSD items and scores demonstrated strong reliability and validity. Implementation of the measures in interventional studies will enable the evaluation of responsiveness and meaningful within-patient change.


Assuntos
Asma , Adolescente , Adulto , Asma/diagnóstico , Humanos , Medidas de Resultados Relatados pelo Paciente , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários
7.
Int Forum Allergy Rhinol ; 12(8): 996-1005, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-34921526

RESUMO

BACKGROUND: This qualitative study assessed the experience of patients with chronic rhinosinusitis with nasal polyposis (NP) to inform the development of a novel symptom diary for clinical study use. METHODS: Concept elicitation and cognitive interviews were conducted with patients who had a physician-verified diagnosis of NP and a history of intranasal corticosteroid use. Concepts were identified via open-ended and follow-up questions. Relative symptom/impact disturbance level was assessed using a scale of 0 (not at all disturbing) to 10 (extremely disturbing). RESULTS: Patients (n = 30) attributed numerous symptoms and impacts to NP; the most prevalent and disturbing were nasal congestion (identified by 100% of patients; average disturbance rating = 7.9), nasal blockage/obstruction (97%; 8.2), difficulty with sense of smell (97%; 7.6), facial pressure (90%; 6.2), postnasal drip (87%; 6.5), runny nose (87%; 6.2), facial pain (80%; 6.3), and headache (77%; 6.5). These symptoms, along with the impact of NP on sleep and daily activities, were included in the Nasal Polyposis Symptom Diary (NPSD). Cognitive interviews confirmed that patients understood the NPSD items and could select a response reflective of their experience at its worst over the past 24 hours using a four-point scale (none, mild, moderate, or severe). CONCLUSION: The most relevant and disturbing symptoms, according to patients with NP, were included in the NPSD. Interviews confirmed the suitability of NPSD in capturing the daily experience of patients. These findings support the content validity of the NPSD as a suitable tool for capturing NP symptoms and impacts.


Assuntos
Obstrução Nasal , Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Pólipos Nasais/diagnóstico , Avaliação de Resultados da Assistência ao Paciente , Rinite/diagnóstico , Sinusite/diagnóstico
8.
Lancet Rheumatol ; 4(3): e198-e207, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38288936

RESUMO

BACKGROUND: The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials but does not include patient-reported outcomes. To evaluate the clinical meaningfulness of a BICLA response from the patient perspective, we aimed to analyse patient-reported outcomes by BICLA responses with anifrolumab or placebo in patients with moderate to severe SLE. METHODS: We did a post-hoc analysis of pooled data from the phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab, which assessed health-related quality of life using the Short Form 36 Health Survey (SF-36; version 2) and Lupus Quality of Life, fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), pain using the Numerical Rating Scale, and disease activity using Patient Global Assessment. Changes from baseline and proportions of patients reporting improvements in patient-reported outcomes greater than or equal to the minimum clinically important differences and scores greater than or equal to the normative values were compared in BICLA responders and non-responders and by treatment group (intravenous anifrolumab 300 mg or placebo). FINDINGS: 726 patients were included in the TULIP trials, of whom 366 received placebo (184 patients in TULIP-1 and 182 in TULIP-2) and 360 received anifrolumab 300 mg (180 patients in each trial). The mean patient age was 41·8 years (SD 11·9). 674 (93%) patients were female, 52 (7%) were male, and 479 (66%) were White; 283 (39%) were BICLA responders and 443 (61%) were BICLA non-responders. Compared with non-responders, BICLA responders reported greater mean improvements from baseline at week 52 in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores (all nominal p<0·0053). Compared with non-responders, a greater proportion of BICLA responders reported improvements greater than or equal to the minimum clinically important difference across all SF-36 domains; eg, Physical Component Summary (165 [60%] of 277 for responders vs 63 [15%] of 416 for non-responders), Mental Component Summary (140 [51%] of 276 vs 59 [15%] of 416), and role physical (184 [70%] of 264 vs 76 [19%] of 398); Lupus Quality of Life domains; eg, physical health (151 [58%] of 262 vs 60 [15%] of 396), and intimate relationships (77 [41%] of 187 vs 33 [11%] of 286), and FACIT-F (155 [56%] of 276 vs 66 [15%] of 439). Similarly, a greater proportion of BICLA responders had scores equal to or greater than the normative values across all SF-36 domains and FACIT-F compared with BICLA non-responders at week 52. Patients who received anifrolumab reported greater numerical improvements in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores than those who received placebo. INTERPRETATION: BICLA responders reported significant and clinically meaningful improvements in Patient Global Assessment, health-related quality of life, fatigue, and pain compared with BICLA non-responders. More patients with moderate to severe SLE who received anifrolumab were BICLA responders and had improved health-related quality of life, fatigue, and pain than those who received placebo. FUNDING: AstraZeneca.

9.
Orphanet J Rare Dis ; 16(1): 495, 2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34819137

RESUMO

BACKGROUND: A patient reported outcome (PRO) instrument with evidence of validity and reliability for assessing symptoms of eosinophilic gastritis (EG) and eosinophilic gastroenteritis (EGE) is needed to measure treatment benefit in clinical trials. The aim of this research is to develop an EG/EGE symptom PRO instrument for patients aged 12 and above. METHODS: The Symptom Assessment for Gastrointestinal Eosinophilic Diseases (SAGED) was developed through a literature review, discussions with expert clinicians, and concept elicitation and cognitive debriefing interviews with patients. Patients (n = 28) were recruited based on confirmed diagnosis and self-reported symptoms. The final instrument was translated and linguistically validated with additional cognitive debriefing interviews (n = 105). RESULTS: SAGED is a 24-h recall questionnaire consisting of eight items evaluating the core symptoms of EG and EGE (abdominal pain, nausea, bloating, early satiety, loss of appetite, vomiting, and diarrhea). Seven of the eight items are evaluated on an 11-point numerical rating scale ranging from 'none' to 'worst imaginable'. Cognitive debriefing interviews showed that adults and adolescents understand the content and are able to select a response that reflects their experience. The linguistic validation process produced 21 translations that are understandable to patients and conceptually equivalent to the source version. CONCLUSIONS: SAGED is suitable for measuring symptom improvement in adult and adolescent patients with EG and/or EGE. The content validity of SAGED has been established through best practices in qualitative research for PRO instrument development. The psychometric properties of SAGED will be evaluated in a future study.


Assuntos
Enterite , Gastrite , Inquéritos e Questionários/normas , Avaliação de Sintomas , Adolescente , Adulto , Criança , Enterite/diagnóstico , Enterite/tratamento farmacológico , Eosinofilia , Gastrite/diagnóstico , Gastrite/tratamento farmacológico , Humanos , Reprodutibilidade dos Testes , Traduções
10.
J Asthma Allergy ; 14: 713-725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211280

RESUMO

BACKGROUND: Health-related quality of life (HRQoL) and productivity of patients with confirmed severe asthma (SA) have not been well characterized in large, real-world populations. PURPOSE: To characterize SA impact on HRQoL, work productivity, and activity impairment in a large, real-world cohort in the United States (US). METHODS: CHRONICLE is an observational study of specialist-treated adults (≥18 years) in the US with SA receiving biologics or maintenance systemic corticosteroids (mSCS), or those persistently uncontrolled by high-dosage inhaled corticosteroids with additional controllers (HD ICS+). At enrollment, patients completed the St. George's Respiratory Questionnaire (SGRQ) and Work Productivity and Activity Impairment (WPAI) questionnaire. Results were analyzed for those enrolled between February 2018 and February 2020. RESULTS: Among patients who completed enrollment questionnaires (n = 1109), mean age was 54 years and most were women (70%). Among SGRQ respondents (n = 960), mean (SD) total score was 43 (23); 51% reported good/very good health. Among WPAI respondents (n = 1057; 566 employed), mean (SD) overall work impairment was 21% (25). Patients receiving biologics (vs mSCS, HD ICS+ only) had better SGRQ total scores (38 vs 59, 48) and lower work impairment (17% vs 34%, 27%). Patients with better SGRQ activity scores relative to symptom scores had better SGRQ impacts scores, total scores, and reported better overall health. CONCLUSION: SA significantly affects HRQoL, work productivity, and activity. The SGRQ is a valuable research instrument for evaluating HRQoL in SA. Due to its association with HRQoL and overall health, activity impairment should be a focus when monitoring patients' disease control. STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

11.
Ann Allergy Asthma Immunol ; 126(5): 576-583.e4, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33333295

RESUMO

BACKGROUND: Atopic dermatitis (AD) is associated with a substantial burden on quality of life (QoL). OBJECTIVE: To evaluate the effects of tralokinumab on health-related QoL in patients with moderate-to-severe AD using patient-reported outcomes. METHODS: This was a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study in adults with moderate-to-severe AD. The patients received subcutaneous tralokinumab or placebo (1:1:1:1) every 2 weeks for 12 weeks and class 3 topical corticosteroid cream or ointment at least once daily from the run-in to end of follow-up. Patient-reported outcome end points were change from baseline to week 12 in the Dermatology Life Quality Index (dermatology life quality index (DLQI); prespecified secondary objective), the Short Form 36 Health Survey (SF-36) version 2, and sleep interference numeric rating scale score (prespecified exploratory objectives). RESULTS: A total of 204 patients were randomized to placebo (n = 51) or tralokinumab (45 mg, n = 50; 150 mg, n = 51; 300 mg, n = 52). Tralokinumab 300 mg every 2 weeks improved total Dermatology Life Quality Index vs placebo at week 12 (placebo-adjusted mean change, -3.51 [95% confidence interval, -6.00 to -1.02]). At week 12, both the mental component summary (4.23 [0.98-7.47]) and the physical component summary (4.26 [1.83-6.69]) and all 8 domains of the Short Form 36 Health Survey were improved in patients treated with tralokinumab 300 mg vs placebo. Sleep interference was improved at week 12 with all tralokinumab doses vs placebo. CONCLUSION: Tralokinumab improved health-related QoL in patients with moderate-to-severe atopic dermatitis, providing further evidence of the value of targeting interleukin-13 in such patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02347176; https://clinicaltrials.gov/ct2/show/NCT02347176.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Qualidade de Vida/psicologia , Sono/efeitos dos fármacos , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Inquéritos Epidemiológicos , Humanos , Interleucina-13/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Placebos/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
12.
J Biol Chem ; 296: 100020, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33144324

RESUMO

Heterodimeric KIF3AC is a mammalian kinesin-2 that is highly expressed in the central nervous system and associated with vesicles in neurons. KIF3AC is an intriguing member of the kinesin-2 family because the intrinsic kinetics of KIF3A and KIF3C when expressed as homodimers and analyzed in vitro are distinctively different from each other. For example, the single-molecule velocities of the engineered homodimers KIF3AA and KIF3CC are 293 and 7.5 nm/s, respectively, whereas KIF3AC has a velocity of 186 nm/s. These results led us to hypothesize that heterodimerization alters the intrinsic catalytic properties of the two heads, and an earlier computational analysis predicted that processive steps would alternate between a fast step for KIF3A followed by a slow step for KIF3C resulting in asymmetric stepping. To test this hypothesis directly, we measured the presteady-state kinetics of phosphate release for KIF3AC, KIF3AA, and KIF3CC followed by computational modeling of the KIF3AC phosphate release transients. The results reveal that KIF3A and KIF3C retain their intrinsic ATP-binding and hydrolysis kinetics. Yet within KIF3AC, KIF3A activates the rate of phosphate release for KIF3C such that the coupled steps of phosphate release and dissociation from the microtubule become more similar for KIF3A and KIF3C. These coupled steps are the rate-limiting transition for the ATPase cycle suggesting that within KIF3AC, the stepping kinetics are similar for each head during the processive run. Future work will be directed to define how these properties enable KIF3AC to achieve its physiological functions.


Assuntos
Cinesinas/química , Proteínas Associadas aos Microtúbulos/química , Modelos Químicos , Animais , Cinesinas/genética , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Fosfatos
13.
Rheumatology (Oxford) ; 60(2): 902-906, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33164088

RESUMO

OBJECTIVES: To establish, amongst Irish rheumatic musculoskeletal disease (RMD) patients, rates of COVID-19 symptoms and positive tests, DMARD adherence and attitudes to virtual clinics. METHODS: An online survey assessing COVID-19 status, RMD diagnoses, adherence and information sources was disseminated via the Arthritis Ireland website and social media channels. RESULTS: There were 1381 respondents with 74.8% on immunosuppressive medication. Symptoms of COVID-19 were reported by 3.7% of respondents of which 0.46% tested positive, consistent with the general Irish population. The frequency of COVID-19 symptoms was higher for respondents with spondyloarthropathy [odds ratio (OR) 2.06, 95% CI: 1.14, 3.70] and lower in those on immunosuppressive medication (OR 0.48, 95% CI: 0.27, 0.88), and those compliant with health authority (HSE) guidance (OR 0.47, 95% CI: 0.25, 0.89). Adherence to RMD medications was reported in 84.1%, with 57.1% using health authority guidelines for information on medication use. Importantly, adherence rates were higher amongst those who cited guidelines (89.3% vs 79.9%, P <0.001), and conversely lower in those with COVID-19 symptoms (64.0% vs 85.1%, P =0.009). Finally, the use of virtual clinics was supported by 70.4% of respondents. CONCLUSION: The rate of COVID-19 positivity in RMD patients was similar to the general population. COVID-19 symptoms were lower amongst respondents on immunosuppressive medication and those adherent to medication guidelines. Respondents were supportive of HSE advice and virtual clinics.


Assuntos
Antirreumáticos/uso terapêutico , Atitude Frente a Saúde , COVID-19/epidemiologia , Adesão à Medicação/estatística & dados numéricos , Doenças Reumáticas/tratamento farmacológico , Adulto , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , COVID-19/fisiopatologia , Cloroquina/uso terapêutico , Doenças do Tecido Conjuntivo/tratamento farmacológico , Estudos Transversais , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Irlanda/epidemiologia , Inibidores de Janus Quinases/uso terapêutico , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Espondiloartropatias/tratamento farmacológico , Telemedicina , Vasculite/tratamento farmacológico
14.
Ann Allergy Asthma Immunol ; 126(2): 187-193, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33169672

RESUMO

BACKGROUND: Patients with severe, uncontrolled asthma experience frequent exacerbations and hospitalization, leading to poor health-related quality of life. In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced exacerbations by up to 71% and improved lung function, asthma control, and health-related quality of life vs placebo. OBJECTIVE: This analysis further assessed the impact of tezepelumab on patient-reported outcomes (PROs) in PATHWAY. METHODS: Adults with severe, uncontrolled asthma were randomized to subcutaneous tezepelumab (70 mg every 4 weeks, 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. PROs were assessed using the asthma control questionnaire-6 (ACQ-6) and the asthma quality of life questionnaire (standardized) for patients aged 12 years or older (AQLQ[S]+12). The proportions of responders (defined by improvements of ≥0.5 in ACQ-6 or AQLQ(S)+12 scores) and patients whose asthma was well-controlled, partially-controlled, or uncontrolled in the tezepelumab and placebo groups were identified. The Asthma Daily Diary questionnaire was used to assess changes in overall symptom severity. RESULTS: Overall, 550 patients were randomized. Up to 82% and 77% of tezepelumab-treated patients were ACQ-6 and AQLQ(S)+12 responders, respectively, compared with 70% and 64% of placebo-treated patients, respectively. The proportions of patients with well-controlled or partially-controlled asthma were higher in the tezepelumab-treated group than in the placebo group. In addition, tezepelumab improved the overall symptom severity. CONCLUSION: Tezepelumab treatment improved PROs vs placebo, as indicated by the higher proportion of ACQ-6 and AQLQ(S)+12 responders and improvements in symptom severity in the tezepelumab dose groups. These data further support the benefits of tezepelumab in patients with severe, uncontrolled asthma.


Assuntos
Antiasmáticos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Asma/tratamento farmacológico , Adolescente , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Inquéritos e Questionários , Adulto Jovem
15.
N Engl J Med ; 381(11): 1023-1034, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31112385

RESUMO

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Eosinófilos/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptores de Interleucina-5/antagonistas & inibidores , Idoso , Antiasmáticos/administração & dosagem , Antiasmáticos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Doença Pulmonar Obstrutiva Crônica/imunologia
16.
J Asthma Allergy ; 12: 21-33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774388

RESUMO

BACKGROUND: Patients with severe, uncontrolled asthma experience debilitating symptoms that result in meaningful reductions to health-related quality of life. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody that reduces exacerbations and improves asthma symptoms for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: The objective of this study was to evaluate improvements in daily asthma-related health status outcomes following treatment with benralizumab. METHODS: Pooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) Phase III studies were analyzed. Patients aged 12-75 years with severe, uncontrolled asthma, and blood eosinophil counts (BEC) ≥300 and ≥150 cells/µL were evaluated. Patients received subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W, first three doses Q4W) or placebo and completed a daily diary reporting rescue medication use, night-time awakening requiring rescue medication use, perceived tiredness, and asthma-related activity impairment. Outcome measures were compared across treatment arms from baseline to end of treatment (EOT) using a mixed-effect model for repeated measures analyses. RESULTS: Patients with BEC ≥300 cells/µL receiving benralizumab Q8W had greater improvements in all patient-reported outcomes at EOT relative to baseline than patients receiving placebo (all nominal P≤0.013). Effects were reported as early as 3 days following the initial dose and sustained throughout treatment for daily and night-time rescue medication use and night-time awakenings requiring rescue medication. For patients with BEC ≥300 and ≥150 cells/ µL, sustained improvements in activity impairment items (all nominal P<0.05) were achieved with benralizumab Q8W at week 2. CONCLUSION: Benralizumab produces sustained reductions by as early as 3 days in rescue medication use and activity impairment for patients with severe, uncontrolled eosinophilic asthma.

17.
J Drugs Dermatol ; 17(12): 1298-1308, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30586262

RESUMO

Background: Psoriasis (PsO) is a chronic inflammatory skin disorder that may be associated with comorbidities, including inflammatory bowel disease (IBD), given common immunopathogenic mechanisms. Whether PsO patients are more likely to suffer from gastrointestinal (GI) signs and symptoms has not been well-characterized. Understanding their prevalence in PsO patients may inform strategies to evaluate for GI signs and symptoms, screen for those at risk for IBD, and guide choice of therapy. Objective: To assess the prevalence of GI signs and symptoms in patients with moderate-to-severe PsO. Methods: An Internet-based survey was conducted to evaluate GI signs and symptoms in patients with self-reported moderate-to-severe PsO and non-PsO controls. The impact of PsO severity and presence of psoriatic arthritis (PsA) [self-reported and/or screened positive on the Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire] on prevalence of GI signs and symptoms was also assessed. The survey included questions about PsO, comorbidities, demographics, and GI signs and symptoms. Questions related to GI signs and symptoms were used to calculate a modified CalproQuest* score to identify patients at increased risk for IBD. Results: Survey responses were collected from 740 PsO patients and 1411 non-PsO controls. With the exception of age, demographics were generally comparable between groups. All six GI signs and symptoms assessed (belly pain, feeling full/bloated, diarrhea, mucus in stool, blood in stool, and unintentional weight loss) were more prevalent in PsO patients compared with non-PsO controls, and a higher proportion of PsO patients also had a positive CalproQuest* result. In addition, both more severe PsO and concomitant PsA were associated with a higher prevalence of GI signs and symptoms and a positive CalproQuest*. Conclusions: This study suggests that PsO patients, including those with PsA, have a higher prevalence of GI signs and symptoms. Physicians should recognize and consider this concern in PsO patient management. J Drugs Dermatol. 2018;17(12):1298-1308.


Assuntos
Doenças Inflamatórias Intestinais/epidemiologia , Psoríase , Adolescente , Adulto , Comorbidade , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/patologia , Internet , Masculino , Pessoa de Meia-Idade , Prevalência , Índice de Gravidade de Doença , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto Jovem
18.
J Biol Chem ; 293(35): 13389-13400, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29991594

RESUMO

Heterodimeric KIF3AC and KIF3AB, two members of the mammalian kinesin-2 family, generate force for microtubule plus end-directed cargo transport. However, the advantage of heterodimeric kinesins over homodimeric ones is not well-understood. We showed previously that microtubule association for entry into a processive run was similar in rate for KIF3AC and KIF3AB at ∼7.0 µm-1 s-1 Yet, for engineered homodimers of KIF3AA and KIF3BB, this constant is significantly faster at 11 µm-1 s-1 and much slower for KIF3CC at 2.1 µm-1 s-1 These results led us to hypothesize that heterodimerization of KIF3A with KIF3C and KIF3A with KIF3B altered the intrinsic catalytic properties of each motor domain. Here, we tested this hypothesis by using presteady-state stopped-flow kinetics and mathematical modeling. Surprisingly, the modeling revealed that the catalytic properties of KIF3A and KIF3B/C were altered upon microtubule binding, yet each motor domain retained its relative intrinsic kinetics for ADP release and subsequent ATP binding and the nucleotide-promoted transitions thereafter. These results are consistent with the interpretation that for KIF3AB, each motor head is catalytically similar and therefore each step is approximately equivalent. In contrast, for KIF3AC the results predict that the processive steps will alternate between a fast step for KIF3A followed by a slow step for KIF3C resulting in asymmetric stepping during a processive run. This study reveals the impact of heterodimerization of the motor polypeptides for microtubule association to start the processive run and the fundamental differences in the motile properties of KIF3C compared with KIF3A and KIF3B.


Assuntos
Cinesinas/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Camundongos , Multimerização Proteica
19.
Respir Med ; 134: 130-138, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29413500

RESUMO

BACKGROUND: There are no validated patient diaries for evaluating respiratory symptoms in idiopathic pulmonary fibrosis (IPF). PURPOSE: To evaluate the performance properties of the chronic obstructive pulmonary disease (COPD) Evaluating Respiratory Symptoms™ (E-RS™: COPD) measure in patients with IPF. METHODS: Concept elicitation and cognitive interviews were conducted with IPF patients to evaluate content validity, including comprehensiveness, relevance, and interpretability of E-RS™ items in this patient population. Secondary analyses of IPF clinical study data were performed to evaluate the scoring structure of the tool. With modifications, reliability, validity, and responsiveness of the instrument (E-RS™: IPF) were evaluated. RESULTS: Qualitative interviews (n = 30) were conducted. During the elicitation interviews (n = 20), concept saturation for IPF respiratory symptoms was achieved; all respiratory symptoms covered by the E-RS™ were endorsed by ≥ 30% of the sample. During cognitive interviews (n = 10), all participants found the items interpretable and relevant. Factor analyses conducted via secondary analysis of IPF clinical study data identified no total score and four symptom scales: Chest, Breathlessness, Cough, and Sputum. Reliability of each scale was high (internal consistency [α] >0.85); 2-day reproducibility (ICC >0.88). Validity was supported through significant (P < 0.0001) relationships with the St. George's Respiratory Questionnaire (SGRQ), the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), and other variables. The scales were responsive to change when evaluated using SGRQ Symptoms, UCSD-SOBQ, and Patient Global Impression of Change as anchors (P < 0.01 to P < 0.0001). CONCLUSION: The E-RS™: IPF is a valid, reliable, and responsive tool for evaluating respiratory symptoms in patients with IPF.


Assuntos
Tosse/etiologia , Dispneia/etiologia , Fibrose Pulmonar Idiopática/complicações , Prontuários Médicos , Idoso , Idoso de 80 Anos ou mais , Tosse/diagnóstico , Estudos Transversais , Dispneia/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
20.
Health Qual Life Outcomes ; 14(1): 104, 2016 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-27424173

RESUMO

BACKGROUND: The morning tends to be the most difficult time of day for many patients with chronic obstructive pulmonary disease (COPD) when symptoms can limit one's ability to perform even simple activities. Morning symptoms have been linked to higher levels of work absenteeism, thereby increasing the already substantial economic burden associated with COPD. A validated patient-reported outcome (PRO) instrument designed to capture morning symptoms will allow for a more comprehensive approach to the evaluation of treatment benefit in COPD clinical trials. METHODS: A qualitative interview study was conducted among a sample of symptomatic adults with COPD. Concept elicitation interviews (n = 35) were conducted to identify COPD morning symptoms, followed by cognitive interviews (n = 21) to ensure patient comprehension of the items, instructions and response options of the draft COPD Morning Symptom Diary (COPD-MSD). All interview transcript data were coded using ATLAS.ti software for content analysis. RESULTS: Mean age of the concept elicitation and cognitive interview sample was 65.0 years (±7.5) and 62.3 years (±8.3), respectively. The study sample represented the full range of COPD severity (Global Initiative for Chronic Lung Disease [GOLD] classifications I-IV) and included a mix of racial backgrounds, employment status and educational achievement. During the concept elicitation interviews, the three most frequently reported morning symptoms were shortness of breath (n = 35/35; 100 %), phlegm/mucus (n = 31/35; 88.6 %), and cough (n = 30/35; 85.7 %). A group of clinical and instrument development experts convened to review the concept elicitation data and develop the initial 32-item draft COPD-MSD. Cognitive interviews indicated subjects found the draft COPD-MSD to be comprehensive, clear, and easy to understand. The COPD-MSD underwent minor editorial revisions and streamlining based on cognitive interviews and input from the experts to yield the final 19-item daily diary. CONCLUSIONS: This study supports the content validity of the new COPD-MSD and positions the diary for quantitative psychometric testing.


Assuntos
Prontuários Médicos , Pacientes/psicologia , Psicometria , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Qualidade de Vida/psicologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Reprodutibilidade dos Testes , Inquéritos e Questionários
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