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1.
Ann Rheum Dis ; 73(1): 48-55, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23942868

RESUMEN

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA). METHODS: Patients were randomised 1:1:1 to placebo, 200 mg CZP every 2 weeks (Q2W) or 400 mg CZP every 4 weeks (Q4W). Patients could have had exposure to one previous tumour necrosis factor (TNF) inhibitor therapy. Primary endpoints were American College of Rheumatology 20% (ACR20) response at week 12 and modified Total Sharp Score change from baseline at week 24. Secondary endpoints included; Psoriatic Arthritis Response Criteria (PsARC) score, Health Assessment Questionnaire Disability Index (HAQ-DI), Psoriasis Area and Severity Index, Leeds Enthesitis Index, Leeds Dactylitis Index, and Modified Nail Psoriasis Severity Index. RESULTS: Of 409 patients randomised, 368 completed 24 weeks of treatment. ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1. There was a statistically significant improvement in physical function from baseline, measured by HAQ-DI in CZP patients compared with placebo (-0.50 vs -0.19, p<0.001) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo (78.3% and 77.0% vs 33.1% (p<0.001)). Sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis and nail disease. Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure. No new safety signals were observed. CONCLUSIONS: Rapid improvements in the signs and symptoms of PsA, including joints, skin, enthesitis, dactylitis and nail disease were observed across both CZP dosing regimens.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Artritis Psoriásica/tratamiento farmacológico , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Inmunosupresores/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Artritis Psoriásica/diagnóstico , Certolizumab Pegol , Método Doble Ciego , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/efectos adversos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Placebos , Polietilenglicoles/efectos adversos , Resultado del Tratamiento
2.
Ann Rheum Dis ; 73(1): 233-7, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23942869

RESUMEN

OBJECTIVES: To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials. METHODS: The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated. RESULTS: 409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses. CONCLUSIONS: Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Artritis Psoriásica/diagnóstico por imagen , Artritis Psoriásica/tratamiento farmacológico , Monitoreo de Drogas/métodos , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Inmunosupresores/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Certolizumab Pegol , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/efectos adversos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Placebos , Polietilenglicoles/efectos adversos , Valor Predictivo de las Pruebas , Radiografía , Resultado del Tratamiento
3.
Ann Rheum Dis ; 73(1): 39-47, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24013647

RESUMEN

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-axSpA (NCT01087762), an ongoing Phase 3 trial in patients with axial spondyloarthritis (axSpA), including patients with ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). METHODS: Patients with active axSpA were randomised 1:1:1 to placebo, CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg every 4 weeks (Q4W). In total 325 patients were randomised. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society 20) response at week 12. Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) linear. RESULTS: Baseline disease activity was similar between AS and nr-axSpA. At week 12, ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (57.7 and 63.6 vs 38.3, p≤0.004). At week 24, combined CZP arms showed significant (p<0.001) differences in change from baseline versus placebo in BASFI (-2.28 vs -0.40), BASDAI (-3.05 vs -1.05), and BASMI (-0.52 vs -0.07). Improvements were observed as early as week 1. Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA subpopulations. Adverse events were reported in 70.4% vs 62.6%, and serious adverse events in 4.7% vs 4.7% of All CZP versus placebo groups. No deaths or malignancies were reported. CONCLUSIONS: CZP rapidly reduced the signs and symptoms of axSpA, with no new safety signals observed compared to the safety profile of CZP in RA. Similar improvements were observed across CZP dosing regimens, and in AS and nr-axSpA patients.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Inmunosupresores/administración & dosificación , Polietilenglicoles/administración & dosificación , Espondiloartritis/tratamiento farmacológico , Espondilitis Anquilosante/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Certolizumab Pegol , Método Doble Ciego , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/efectos adversos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Placebos , Polietilenglicoles/efectos adversos , Espondiloartritis/diagnóstico , Espondilitis Anquilosante/diagnóstico , Resultado del Tratamiento
4.
Int J Radiat Biol ; 76(9): 1265-71, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10993637

RESUMEN

PURPOSE: L-selectin (CD62L) is a prerequisite for leucocyte adhesion to endothelial cells of blood vessels and consequently for transmigration. Its expression on the cell surface therefore regulates the ability of lymphocytes to enter lymph nodes, to re-enter blood vessels or to invade tissues at sites of inflammation. The aim of this study was to determine the expression of CD62L on apoptotic lymphocytes after UVB irradiation. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from peripheral blood of normal healthy volunteers. Cells were stimulated with phorbol myristate acetate (PMA) and ionomycin for activation. Apoptosis in peripheral T-cells and Jurkat cells was induced by irradiation with UVB (120 mJ/cm2). In addition, T-cells or Jurkat cells were cultured for the indicated time with anti-Fas antibody CH11. The CH11-induced apoptosis was inhibited by the pan-caspase inhibitor zVAD-fmk. For detection of apoptosis, cells were analysed by cytofluorometry for morphological changes typical for apoptosis. The reliability of the apoptotic cell gate was confirmed by staining with FITC-labelled annexin-V in the presence ofpropidium iodide (PI). For FACS analysis of CD62L expression on the cell-surface immunofluorescence was performed using FITC-conjugated anti-CD62L and PE-conjugated anti-CD3 antibodies. Soluble CD62L (sCD62L) in the cell supernatants was measured by standard ELISA technique. Assays were performed in the presence and absence of metalloprotease inhibitor KB8301. RESULTS: PBMC from healthy volunteers undergoing apoptosis following UVB irradiation selectively shed CD62L, whereas the expression of the lineage-specific marker CD3 showed only minor changes. Shedding was blocked by the hydroxamic acid-based metalloprotease inhibitor KB8301. When Jurkat cells were treated with the caspase inhibitor zVAD-fmk, anti-CD95 antibodies did not induce apoptosis, and the expression of CD62L remained unaltered. CONCLUSION: UVB or ionizing radiation induce apoptosis in lymphocytes. The loss of CD62L is associated with apoptosis and will influence lymphocyte trafficking and, by excluding them from CD62L-mediated adhesion and tissue invasion, might contribute to the regulation of inflammation.


Asunto(s)
Apoptosis/efectos de la radiación , Selectina L/metabolismo , Metaloendopeptidasas/metabolismo , Linfocitos T/efectos de la radiación , Rayos Ultravioleta , Clorometilcetonas de Aminoácidos/farmacología , Anexina A5/metabolismo , Complejo CD3/metabolismo , Adhesión Celular , Separación Celular , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Células Jurkat , Cinética , Selectina L/biosíntesis , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/efectos de la radiación , Fenotipo , Linfocitos T/patología , Factores de Tiempo , Receptor fas/inmunología
5.
Cell Death Differ ; 7(10): 911-5, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11279536

RESUMEN

Exposure of phosphatidylserine on the outer leaflet of the cytoplasmic membrane is an early event during apoptotic cell death and serves as a recognition signal for phagocytes. Usually the clearance of apoptotic cells does not initiate inflammation or immune response. We investigated the immune response in Balb/c mice towards apoptotic human T-cells. Animals injected with apoptotic cells showed significantly reduced humoral immune responses, especially Th1-dependent IgG2a titres, compared to controls immunised with viable cells. However, treatment of apoptotic cells with annexin V (AxV) significantly increased the humoral immune response. AxV binds with high affinity to anionic phospholipids and as a result interferes with the phosphatidylserine recognition by phagocytes. Our results indicate that AxV treatment may be used to increase the efficiency of apoptotic cell-based vaccines, e.g. some tumour vaccines.


Asunto(s)
Anexina A5/inmunología , Anexina A5/farmacología , Apoptosis/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Ratones , Ratones Endogámicos BALB C , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Unión Proteica/inmunología
6.
Scand J Immunol ; 47(4): 343-7, 1998 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9600315

RESUMEN

Apoptotic cells, e.g. postinflammatory neutrophils, were reported to be engulfed by phagocytes without induction of an inflammatory response. We investigated the humoral immune response of BALB/c mice after repeated injection of viable or apoptotic human T cells. Following interleukin-2 (IL-2) deprivation, phytohaemagglutinin (PHA)/IL-2 expanded human T-cell lines were irradiated with UV-B light to induce apoptosis, confirmed by propidium iodide staining of Triton X-100-lysed cells. Indirect immunofluorescence was used to detect antilymphocyte antibodies 7 days after each injection. We found high levels of antilymphocyte antibodies in all animals immunized with viable T cells, whereas animals injected with apoptotic cells showed a significantly reduced humoral immune response. We conclude that apoptotic cells induce poor xenoreactive T-cell responses when compared with viable cells.


Asunto(s)
Apoptosis/inmunología , Linfocitos T/inmunología , Animales , Línea Celular , Supervivencia Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Linfocitos T/trasplante
7.
Arch Otolaryngol Head Neck Surg ; 124(2): 143-8, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9485104

RESUMEN

OBJECTIVE: To assess relationships between voice satisfaction and global quality of life in patients who have been treated for laryngeal cancer. DESIGN: Cross-sectional survey study. SETTING: Veterans Affairs Medical Center. PATIENTS: Eighty patients who had completed treatment for laryngeal cancer with either total laryngectomy (n=17), radiotherapy (n=24), or both (n=39). MAIN OUTCOME MEASURES: Subscale scores on a general health status instrument (the Medical Outcomes Study 36-item short-form health survey), and a validated voice-specific functional status instrument (the Voice Handicap Index). RESULTS: Self-rated global health did not correlate significantly with emotional, functional, or physical voice handicap, although some subscales on the 36-item short-form health survey correlated with voice handicap scores. Global health status scores did not differ between patients who had undergone laryngectomy with a tracheoesophageal puncture and patients treated with radiotherapy only. Physical voice handicap scores did not differ significantly between those who underwent tracheoesophageal puncture and those who had radiotherapy, but emotional (P=.07) and functional (P=.01) handicap scores were lower in patients treated with radiotherapy. However, there was considerable overlap in voice handicap scores, with many patients who had had tracheoesophageal puncture showing less voice handicap than patients treated with radiotherapy. CONCLUSIONS: These data demonstrate that health status is affected by other factors than voice handicap in patients with laryngeal cancer. In addition, there is a large amount of individual variation in voice handicap after treatment. These findings illustrate the need for prospective studies assessing voice handicap and quality of life after treatment for laryngeal cancer.


Asunto(s)
Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirugía , Evaluación de Resultado en la Atención de Salud , Calidad de Vida , Trastornos de la Voz/rehabilitación , Actividades Cotidianas , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Estado de Salud , Humanos , Neoplasias Laríngeas/rehabilitación , Masculino , Persona de Mediana Edad , Trastornos de la Voz/etiología , Trastornos de la Voz/psicología , Calidad de la Voz
9.
Q J Exp Psychol A ; 48(3): 536-72, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7568991

RESUMEN

The role of central motor processes in rehearsal was investigated by studying a brain-damaged patient with a severe articulatory impairment. Evidence is presented that his articulatory impairment is due to a disruption of motor programming rather than to peripheral muscle weakness. Despite his motor programming deficit, the patient showed normal auditory span and evidence of rehearsal for auditorily presented sequences of words. For visual presentation, span was reduced and there was no evidence of rehearsal. Also, the patient showed excellent sentence comprehension for syntactically complex sentences for both auditory and visual presentation. The results imply that central motor processes are not critical for normal short-term memory, at least for auditory presentation, and that reading comprehension does not depend on inner rehearsal.


Asunto(s)
Trastornos de la Articulación/psicología , Daño Encefálico Crónico/psicología , Memoria a Corto Plazo , Práctica Psicológica , Lectura , Percepción del Habla , Trastornos de la Articulación/fisiopatología , Atención/fisiología , Encéfalo/fisiopatología , Daño Encefálico Crónico/fisiopatología , Humanos , Masculino , Memoria a Corto Plazo/fisiología , Persona de Mediana Edad , Neuronas Motoras/fisiología , Pruebas Neuropsicológicas , Fonética , Percepción del Habla/fisiología , Conducta Verbal/fisiología
10.
Cognition ; 32(2): 157-91, 1989 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-2752707

RESUMEN

This research evaluated Grodzinsky's (1984, 1986a) syntactic loss and Kolk and van Grunsven's (1985) working memory impairment explanations of syntactic comprehension deficits in agrammatic aphasics. Four aphasic patients were evaluated who showed different patterns of impairment on morphological and structural aspects of production. The comprehension tasks compared performance on full and truncated passive sentences. The syntactic loss hypothesis predicted worse performance on truncated than full passives, while the working memory deficit hypothesis predicted the reverse. Neither hypothesis was supported, as the patients performed at a similar level on both types of passives. In addition, there was little relation between the patients' production indices and their comprehension level. The results argue against any global theory of agrammatism that attempts to attribute all agrammatic speech and co-occurring syntactic comprehension deficits to the same source.


Asunto(s)
Afasia de Broca/psicología , Afasia/psicología , Lingüística , Memoria a Corto Plazo , Anciano , Humanos , Persona de Mediana Edad , Teoría Psicológica , Habla
11.
Brain Lang ; 28(2): 196-234, 1986 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-3730815

RESUMEN

The syntactic abilities of a mild Wernicke's aphasic were examined in production and comprehension tasks. The patient made few errors involving the omission or substitution of substantives or grammatical markers, especially after the first few weeks of testing. Despite his good ability to produce sentences with acceptable surface form, he continued to make role reversal errors and to produce a restricted range of syntactic forms. In comprehension, he also demonstrated an impairment in his ability to use the syntactic information in a sentence to assign role relations. These syntactic impairments could not be attributed to a short-term memory deficit as the patient showed only a slightly reduced short-term memory span, and showed evidence of having a normal phonological store. Implications for theories of aphasic deficits as well as for theories of normal language processing are discussed.


Asunto(s)
Afasia de Wernicke/psicología , Afasia/psicología , Lenguaje , Humanos , Masculino , Memoria a Corto Plazo , Persona de Mediana Edad , Teoría Psicológica , Lectura , Percepción del Habla , Conducta Verbal
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