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1.
Am J Respir Crit Care Med ; 204(2): 209-221, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33651671

RESUMO

Rationale: Systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. Objectives: We investigated the safety and efficacy of B-cell depletion for SSc-PAH. Methods: In an NIH-sponsored, multicenter, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 patients with SSc-PAH on stable-dose standard medical therapy received two infusions of 1,000 mg rituximab or placebo administered 2 weeks apart. The primary outcome measure was the change in 6-minute-walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug responsiveness. Measurements and Main Results: We randomized 57 subjects from 2010 to 2018. In the primary analysis, using data through Week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6 ± 11.1 m vs. 0.5 ± 9.7 m; P = 0.12). Although a negative study, when data through Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 ± 8.8 m for rituximab and 0.4 ± 7.4 m for placebo (P = 0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (receiver operating characteristic area under the curve, 0.88-0.95). Conclusions: B-cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Future studies in these patients can confirm whether the identified biomarkers predict rituximab responsiveness. Clinical trial registered with www.clinicaltrails.gov (NCT01086540).


Assuntos
Linfócitos B/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/etiologia , Rituximab/uso terapêutico , Escleroderma Sistêmico/complicações , Adolescente , Adulto , Idoso , Biomarcadores Farmacológicos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Rheumatology (Oxford) ; 59(7): 1505-1513, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628482

RESUMO

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Proteína C-Reativa/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lovastatina/uso terapêutico , Adulto , Anticorpos Antiproteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Arthritis Rheum ; 65(4): 1097-106, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23334994

RESUMO

OBJECTIVE: To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as to investigate its mechanisms. METHODS: Patients with primary Sjögren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression. RESULTS: Twelve female patients with primary Sjögren's syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature. CONCLUSION: In patients with primary Sjögren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Linfócitos B/citologia , Fatores Imunológicos/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Fatores Imunológicos/efeitos adversos , Contagem de Linfócitos , Pessoa de Meia-Idade , Estudos Prospectivos , Rituximab , Síndrome de Sjogren/sangue , Resultado do Tratamento
4.
JAMA Neurol ; 72(2): 159-69, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25546364

RESUMO

IMPORTANCE: Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS. OBJECTIVE: To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT. DESIGN, SETTING, AND PARTICIPANTS: Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled. INTERVENTIONS: Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. MAIN OUTCOMES AND MEASURES: The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS: Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores. CONCLUSIONS AND RELEVANCE: At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/farmacologia , Esclerose Múltipla Recidivante-Remitente , Resultado do Tratamento , Adulto , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/cirurgia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos
5.
Stat Interface ; 3(1): 81-90, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25083169

RESUMO

The diffusion tensor imaging (DTI) protocol characterizes diffusion anisotropy locally in space, thus providing rich detail about white matter tissue structure. Although useful metrics for diffusion tensors have been defined, statistical properties of the measures have been little studied. Assuming homogeneity within a region leads to being able to apply Wishart distribution theory. First, it will be shown that common DTI metrics are simple functions of known test statistics. The average diffusion coefficient (ADC) corresponds to the trace of a Wishart, and is also described as the generalized (multivariate) variance, the average variance of the principal components. Therefore ADC has a known exact distribution (a positively weighted quadratic form in Gaussians) as well as a simple and accurate approximation (Satterthwaite) in terms of a scaled chi square. Of particular interest is that fractional anisotropy (FA) values for given regions of interest are functions of the Geisser-Greenhouse (GG) sphericity estimator. The GG sphericity estimator can be approximated well by a linear transformation of a squared beta random variable. Simulated data demonstrates that the fits work well for simulated diffusion tensors. Applying traditional density estimation techniques for a beta to histograms of FA values from a region allow representing the histogram of hundreds or thousands of values in terms of just two estimates for the beta parameters. Thus using the approximate distribution eliminates the "curse of dimensionality" for FA values. A parallel result holds for ADC.

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