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1.
Clin Rheumatol ; 37(9): 2381-2390, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30078086

RESUMEN

The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Progresión de la Enfermedad , Artritis Reumatoide/sangre , Azetidinas/uso terapéutico , Proteína C-Reactiva/análisis , Método Doble Ciego , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Oportunidad Relativa , Purinas , Pirazoles , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
2.
Arthritis Rheumatol ; 69(5): 943-952, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28029752

RESUMEN

OBJECTIVE: To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis. METHODS: Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups. RESULTS: Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. CONCLUSION: Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.


Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Azetidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Antirreumáticos/uso terapéutico , Apolipoproteína A-I/metabolismo , Apolipoproteína C-III/metabolismo , Apolipoproteínas B/metabolismo , Artritis Reumatoide/metabolismo , Azetidinas/uso terapéutico , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Lipoproteína(a)/metabolismo , Masculino , Persona de Mediana Edad , Purinas , Pirazoles , Proteína Amiloide A Sérica/metabolismo , Índice de Severidad de la Enfermedad , Sulfonamidas/uso terapéutico , Triglicéridos/metabolismo
3.
Arthritis Rheumatol ; 69(3): 643-654, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27723281

RESUMEN

OBJECTIVE: To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab. METHODS: Patient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString. RESULTS: At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti-double-stranded DNA (anti-dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti-dsDNA antibody, C3, and immunoglobulin levels. CONCLUSION: SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE-1 and ILLUMINATE-2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Factor Activador de Células B/antagonistas & inhibidores , Expresión Génica/genética , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
4.
Patient Prefer Adherence ; 3: 31-43, 2009 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-19936143

RESUMEN

BACKGROUND: Premature discontinuation of treatment impacts outcomes of clinical practice. The traditional perception has been patient discontinuation is mainly driven by unwanted side effects. Systematic analysis of data from clinical trials across several disease states was performed to identify predictors of premature discontinuation during clinical interventions. METHODS: A post hoc analysis was conducted on 22 randomized, double-blind, placebo-controlled clinical trials for treatment of fibromyalgia, diabetic peripheral neuropathic pain, major depressive disorder, and generalized anxiety disorder. Analyses were conducted on pooled data within each disease state. RESULTS: Lack of early therapeutic response was a significant predictor of patient discontinuation in each disease state. Visit-wise changes in therapeutic response and severity of adverse events were also significant risk factors, with change in therapeutic response having a higher significance level in three disease states. Patients who discontinued due to adverse events had similar therapeutic responses as patients completing treatment. CONCLUSION: Contrary to the conventional belief that premature treatment discontinuation is primarily related to adverse events, our findings suggest lack of therapeutic response also plays a significant role in patient attrition. This research highlights the importance of systematic monitoring of therapeutic response in clinical practice as a measure to prevent patients' discontinuation from pharmacological treatments.

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