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BACKGROUND: Definitions of trial measures are consequential to accurately capturing outcomes and cross-trial comparability, particularly for derivative measures. OBJECTIVE: Using CombiRx, examine the impact of relapse definition on endpoints and evaluate the durability of progression measures in Relapsing Remitting Multiple Sclerosis (RRMS). METHODS: CombiRx relapse types were distinguished by the presence or timing of Expanded Disability Status Scale (EDSS) increase. Using the broadest definition of relapse, progression endpoints were assessed in patients without relapses on trial. Durability compared EDSS at study end and time of worsening. RESULTS: Broadening relapse definition to the most inclusive definition increased annualized relapse rate (ARR) threefold in all arms and decreased progression independent of relapse activity (PIRA), defined as 6-month confirmed disability worsening (6M CDW) without relapse, by 44%. Neither PIRA nor PIA (progression independent of any inflammatory activity) guaranteed durable worsening, with 43% and 40%, respectively, improving by end of study. Multivariate analysis showed two CDW events, not relapse, predicted durability among patients meeting 6M CDW. CONCLUSIONS: The stringency of relapse definition impacted absolute ARR and composite endpoints in RRMS. Despite the most generous relapse definition, 43% of patients meeting PIRA on trial did not have durable worsening suggesting that relapse definition and durability should be considered to avoid overestimating progression in RRMS trials.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Doença Crônica , Progressão da DoençaRESUMO
Neurofibromatosis 1 (NF1) is a common genetic disorder typically diagnosed in childhood and characterized by cutaneous findings, nerve sheath tumors, skeletal abnormalities, malignancies, and developmental differences. Due to its variability, NF1 is an unpredictable condition that parents have concerns about discussing with their children. While there are publications addressing the disclosure of genetic conditions in general, no NF1-specific disclosure literature exists. To fill this gap, this mixed methods study sought to evaluate the concerns, barriers, failures, or successes parents or guardians have experienced when they have or have not chosen to tell their child(ren) about an NF1 diagnosis. Parents of children between ages 0 and 17 with a diagnosis of NF1 completed a survey and some parents were selected for an interview invitation. A total of 258 surveys were completed, and 20 parents were interviewed. Interview transcripts were categorized into disclosure and non-disclosure groups. Themes were organized into five categories based on interview questions: disclosure concerns, factors affecting disclosure/non-disclosure, approaches to disclosure, desired resources, and recommendations for disclosure. Sentiment analysis was performed on responses about the disclosure discussion itself. Results indicated that most parents (70.5%) disclosed the NF1 diagnosis to their child and overall felt it was a positive experience. Almost one-third of parents (29.5%) had not disclosed the diagnosis. A strong significance was identified between disclosure and severe presentation of NF1 (p = 0.0008). Parents in both groups shared similar concerns about discussing the diagnosis and multiple factors influenced the disclosure decision. Most parents approached disclosure as a process and emphasized the need to be honest and supportive of their child. Parents highlighted the need for more educational resources for children and guidance on how to disclose. These findings indicate that additional resources and support for parents would facilitate disclosure and the involvement of genetic counselors in the process would be beneficial.
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OBJECTIVE: To determine differences in obesity, type 2 diabetes, and hypertension in Black patients compared with White patients with multiple sclerosis (MS). DESIGN: Cross-sectional database review. SETTING: Large academic medical center research records database. PARTICIPANTS: A total of 3191 patient cases (N=3191; 77% female, 34% Black) identified by MS diagnosis within the medical record. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Diagnosis codes for type 2 diabetes and hypertension. Body mass index (BMI), race, age, and sex were collected. Analysis of variance (continuous variables) and chi-square analyses (categorical variables) were conducted to determine differences in obesity, diabetes, and hypertension between race and sex. Logistic regression was conducted to determine odds ratios (ORs) of developing diabetes and hypertension based on race, sex, BMI, and age. RESULTS: Black patients were more than twice as likely to be diagnosed as having diabetes (OR, 2.15 [95% CI, 1.70-2.72]; P<.0001) or hypertension (OR, 2.44 [95% CI, 2.05-2.91], P<.0001) compared with White patients. Sex did not present a greater likelihood of being diagnosed as having diabetes; however, men were 1.22 times more likely be diagnosed as having hypertension compared with women (95% CI, 1.01-1.49; P=.0439). Increased age and BMI were also significantly associated with likelihood of diagnosis of diabetes and hypertension (age: diabetes OR, 1.05 [95% CI, 1.04-1.06], P<.0001; hypertension OR, 1.06 [95% CI, 1.05-1.06], P<.0001; BMI: diabetes obese vs normal: OR, 2.11 [95% CI, 1.43-3.11], P=.0002; hypertension: obese vs normal: OR, 1.72 [95% CI, 1.39-2.13], P<.0001). CONCLUSIONS: Black patients with MS are significantly more likely to have cardiometabolic conditions than White patients. These conditions have been associated with poorer health outcomes for people with MS and may have some effect on the differences in MS disease course reported in Black patients.
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Diabetes Mellitus Tipo 2 , Hipertensão , Esclerose Múltipla , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , População BrancaRESUMO
BACKGROUND: The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis). OBJECTIVE: To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis. DESIGN: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341). SETTING: Academic and community-based rheumatology, gastroenterology, and dermatology practices. PATIENTS: Adults aged 50 years or older receiving TNFis for any indication. INTERVENTION: Random assignment to ZVL versus placebo. MEASUREMENTS: Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid. RESULTS: Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL (n = 310) or placebo (n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively. LIMITATION: Potentially limited generalizability to patients receiving other types of immunomodulators. CONCLUSION: This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics. PRIMARY FUNDING SOURCE: The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.
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Varicela/prevenção & controle , Vacina contra Herpes Zoster , Herpes Zoster/prevenção & controle , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Vacinas Atenuadas , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Varicela/epidemiologia , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , ELISPOT , Feminino , Herpes Zoster/epidemiologia , Herpesvirus Humano 3/imunologia , Humanos , Imunogenicidade da Vacina , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To retrospectively compare frequency of contact lens (CL) complications in soft CL users of hydrogen peroxide (H2O2) and multipurpose solutions (MPS). METHODS: This was a multicenter, retrospective chart review of CL records from each patient's three most recent eye examinations at academic and private practices. Patients must have used the same solution type for at least 3 years. Univariate analyses were conducted using t tests, and chi-square or Fisher's exact test for categorical measures. RESULTS: There were 1,137 patients included, with 670 (59%) using MPS and 467 (41%) H2O2. In total, 706 (62%) experienced at least one complication; 409 used MPS and 297 used H2O2. There was no difference in the proportion of patients experiencing at least one complication between MPS (61%) and H2O2 (64%) (P=0.38). Multipurpose solutions users were more likely to report discomfort compared with H2O2 users (P=0.04). Presumed microbial keratitis was experienced by 16 MPS and nine H2O2 users (P=0.60). CONCLUSIONS: No significant differences were found in the frequency of CL complications between MPS and H2O2. H2O2 users were less likely to report discomfort and thus switching to a H2O2 system may be an alternative in CL users with discomfort.
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Lentes de Contato Hidrofílicas , Ceratite , Soluções para Lentes de Contato/efeitos adversos , Humanos , Peróxido de Hidrogênio/efeitos adversos , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
Human immunodeficiency virus-seronegative men aged 15-22 years who lost bone mineral density (BMD) during tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) showed BMD recovery 48 weeks following PrEP discontinuation. Lumbar spine and whole body BMD z-scores remained below baseline 48 weeks off PrEP in participants aged 15-19 years. Clinical Trials Registration. NCT01772823 (ATN 110) and NCT01769456 (ATN 113).
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Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Adolescente , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Densidade Óssea , Emtricitabina/farmacologia , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Humanos , Masculino , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Adulto JovemRESUMO
Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.
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Proteínas do Sistema Complemento/genética , Redes Reguladoras de Genes/genética , Esclerose Múltipla/genética , Degeneração Neural/genética , Vias Visuais/fisiopatologia , Adulto , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Feminino , Seguimentos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Retina/patologia , Tomografia de Coerência ÓpticaRESUMO
OBJECTIVE: We implemented a nontargeted, opt-out HCV testing and linkage to care (LTC) program in an academic tertiary care emergency department (ED). Despite research showing the critical role of ED-based HCV testing programs, predictors of LTC have not been defined for patients identified through the nontargeted ED testing strategy. In order to optimize health outcomes for patients with HCV, we sought to identify predictors of LTC failure. METHODS: This was a retrospective cohort study of adult patients who were tested for HCV in the ED between August 2015 and September 2018 and were confirmed to have chronic HCV infection through RNA testing. We used logistic regression to assess the relationship between candidate predictors and the primary outcome, LTC failure, which was defined as a patient not being seen by an HCV treating provider after discharge from the ED. RESULTS: Of 53,297 patients tested, 1,674 (3.1%) had HCV on confirmatory testing, and 355 (21%) linked to care. Predictors of LTC failure included younger age (OR 0.96, 95% CI 0.95-0.97), white race (OR 1.65, 95% CI 1.23-2.22), homelessness (OR 1.91, 95% CI 1.19-3.08), substance use (OR 1.77, 95% CI 1.34-2.34), and comorbid psychiatric illness (OR 2.16, 95% CI 1.59-2.94). Patients with significant medical comorbidities (OR 0.57, 95% CI 0.41-0.78) or HIV co-infection (OR 0.11, 95% CI 0.03-0.46) were less likely to experience LTC failure. CONCLUSIONS: One in five HCV-infected patients identified by ED-based nontargeted testing successfully linked to an HCV treating provider. Predictors of LTC failure may guide the development of targeted interventions to improve LTC success.
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Continuidade da Assistência ao Paciente/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Hepatite C Crônica/diagnóstico , Transtornos Mentais/epidemiologia , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Fatores Etários , Alabama/epidemiologia , Estudos de Coortes , Comorbidade , Serviço Hospitalar de Emergência , Feminino , Infecções por HIV/epidemiologia , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/sangue , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/terapia , Pessoas Mal Alojadas/estatística & dados numéricos , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , RNA Viral/sangue , Estudos Retrospectivos , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
BACKGROUND: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. OBJECTIVES: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. METHODS: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. RESULTS: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. CONCLUSION: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.
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Avaliação da Deficiência , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Projetos de Pesquisa , Adolescente , Adulto , Interpretação Estatística de Dados , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Determinação de Ponto Final , Feminino , Acetato de Glatiramer/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Interferon beta-1a/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Projetos de Pesquisa/estatística & dados numéricos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement. METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14â weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12â weeks. Total serum type I IFN activity, IFN-α and IFN-ß activity were measured using a functional reporter cell assay. RESULTS: In the test set, an increased ratio of IFN-ß to IFN-α (IFN-ß/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-ß/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-ß/α activity ratio (p=0.005). CONCLUSIONS: Increased pretreatment serum IFN-ß/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Interferon-alfa/sangue , Interferon beta/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto JovemRESUMO
Blacks in the USA, including black men who have sex with men (MSM), tend to have stronger religious and spiritual affiliations compared with other racial/ethnic populations. HIV and STD incidence rates continue to rise among Black MSM. Using data from the CDC Brothers y Hermanos (ByHS) project, this study examined correlations between high-risk behavior, e.g., substance use and high-risk sexual behavior (e.g., condom use history, unprotected sexual intercourse, HIV infection status, and STD infection status) religiosity, spirituality, age, among Black MSM (N = 1141). This exploratory study examined whether religiosity and spirituality were associated with high-risk behavior and high-risk sexual behavior among Black MSM. Religiosity and spirituality indices were compiled from the ByHS data. The religiosity index was significantly associated with HIV infection and use of cocaine, crack, and poppers as well as marginally associated with ecstasy use. Spirituality was significantly associated with HIV infection status, STD infection status, alcohol use, and crack use. Given these relationships, current and future HIV prevention models targeting Black MSM should consider the potential importance of the roles of religiosity and spirituality in the lives of Black MSM to increase the efficacy of risk reduction interventions.
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Negro ou Afro-Americano/estatística & dados numéricos , Infecções por HIV/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Homossexualidade Masculina/estatística & dados numéricos , Religião , Sexo sem Proteção/estatística & dados numéricos , Adolescente , Adulto , Negro ou Afro-Americano/psicologia , Idoso , Homossexualidade Masculina/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Philadelphia , Fatores de Risco , Assunção de Riscos , Espiritualidade , Sexo sem Proteção/psicologia , Adulto JovemRESUMO
HIV infection rates continue to disproportionately affect Black men who have sex with men (Black MSM) compared to other groups. Research has shown that higher rates of substance use and higher levels of depression are positively correlated with higher sexual risk behavior, and little research has examined relationships between high levels of religiosity and spirituality prevalent in Black culture and issues of substance use and depression among Black MSM. This study did just that and found a relationship between religiosity, spirituality, and risk behavior. These relationships suggest that future HIV prevention models might incorporate religiosity and spirituality to increase the efficacy of risk reduction interventions for Black MSM.
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Negro ou Afro-Americano/psicologia , Transtorno Depressivo/psicologia , Homossexualidade Masculina/psicologia , Religião e Psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Transtorno Depressivo/complicações , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Assunção de Riscos , Parceiros Sexuais/psicologia , Espiritualidade , Transtornos Relacionados ao Uso de Substâncias/complicações , Adulto JovemRESUMO
A comprehensive analysis of the effect of lesion in-painting on the estimation of cortical thickness using magnetic resonance imaging was performed on a large cohort of 918 relapsing-remitting multiple sclerosis patients who participated in a phase III multicenter clinical trial. An automatic lesion in-painting algorithm was developed and implemented. Cortical thickness was measured using the FreeSurfer pipeline with and without in-painting. The effect of in-painting was evaluated using FreeSurfer's paired analysis pipeline. Multivariate regression analysis was also performed with field strength and lesion load as additional factors. Overall, the estimated cortical thickness was different with in-painting than without. The effect of in-painting was observed to be region dependent, more significant in the left hemisphere compared to the right, was more prominent at 1.5 T relative to 3 T, and was greater at higher lesion volumes. Our results show that even for data acquired at 1.5 T in patients with high lesion load, the mean cortical thickness difference with and without in-painting is â¼2%. Based on these results, it appears that in-painting has only a small effect on the estimated regional and global cortical thickness. Hum Brain Mapp 36:3749-3760, 2015. © 2015 Wiley Periodicals, Inc.
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Córtex Cerebral/patologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/patologia , Adolescente , Adulto , Algoritmos , Estudos de Coortes , Método Duplo-Cego , Campos Eletromagnéticos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/patologia , Análise Multivariada , Adulto JovemRESUMO
OBJECTIVE: A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon ß-1a (IFN) 30 µg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis. METHODS: A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. RESULTS: Combination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. INTERPRETATION: Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences.
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Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Peptídeos/uso terapêutico , Adolescente , Adulto , Análise de Variância , Estudos de Casos e Controles , Avaliação da Deficiência , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Acetato de Glatiramer , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Prevenção Secundária , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA. METHODS: In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2. RESULTS: Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar. CONCLUSION: These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Artrite Reumatoide/diagnóstico , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Etanercepte , Feminino , Nível de Saúde , Humanos , Hidroxicloroquina/uso terapêutico , Imunoglobulina G/uso terapêutico , Articulações/patologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Índice de Gravidade de Doença , Sulfassalazina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. METHODS: This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. RESULTS: At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). CONCLUSION: Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Imunoglobulina G/administração & dosagem , Imunoglobulina G/uso terapêutico , Metotrexato/uso terapêutico , Receptores do Fator de Necrose Tumoral/administração & dosagem , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Antirreumáticos/administração & dosagem , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Sulfassalazina/administração & dosagem , Sulfassalazina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Large pragmatic clinical trials (PCTs) are increasingly used to conduct comparative effectiveness research. In the context of planning a safety PCT of the live herpes zoster vaccine in rheumatoid arthritis (RA) patients aged ≥ 50 years receiving anti-tumor necrosis factor (TNF) therapy, we evaluated the use of health plan combined with registry data to assess the feasibility of recruiting the 4000 patients needed for the trial and to facilitate site selection. METHODS: Using national US data from Medicare, we identified older RA patients who received anti-TNF therapy in the last quarter of 2009. Extrapolations were made from the Medicare patient population to younger patients and those with other types of insurance using the Consortium of Rheumatology Researchers of North America (CORRONA) disease registry. Patients' treating rheumatologists were grouped into practices and sorted by size from the greatest to the least number of eligible patients. RESULTS: Approximately 50,000 RA patients receiving anti-TNF therapy were identified in the Medicare data, distributed across 1980 physician practices. After augmenting Medicare data with information from CORRONA and extrapolating to younger patients and those with other types of insurance, more than 12,000 potentially eligible study subjects were identified from the 50 largest rheumatology practices. CONCLUSION: Health plan and registry databases appear useful to assess feasibility of large pragmatic trials and to assist in selection of recruitment sites with the greatest number of potentially eligible patients. This novel approach is applicable to trials with simple inclusion/exclusion criteria that can be readily assessed in these data sources.
Assuntos
Bases de Dados Factuais , Medicare , Seleção de Pacientes , Ensaios Clínicos Pragmáticos como Assunto/métodos , Sistema de Registros , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Simulação por Computador , Estudos de Viabilidade , Herpes Zoster/complicações , Herpes Zoster/prevenção & controle , Vacina contra Herpes Zoster , Humanos , Pessoa de Meia-Idade , Estados UnidosRESUMO
BACKGROUND: and purpose Participant recruitment is central to all clinical trials. Any delay in recruitment affects the completion and ultimate success of the trial. We report our experience with patient screening and randomization in CombiRx, which may inform the design of other trials. CombiRx was a multicenter, phase III, double-blind, randomized clinical trial comparing the combined use of interferon beta-1a and glatiramer acetate to either agent alone in patients with relapsing-remitting multiple sclerosis (RRMS). This trial was launched in January 2005 in 69 centers in the United States and Canada under a co-operative agreement with the National Institute of Neurological Disorders and Stroke (NINDS). The goal was to recruit 1000 patients over 1.5 years after a 6-month start-up period. Instead, the investigators required 4.25 years to enroll 1008 patients. METHODS: During this trial, we assessed the effectiveness of various recruitment strategies, utility of rescreening prior screen failures, and potential factors and strategies used in study conduct, research, and infrastructure, all of which affected recruitment of participants and ultimately time to completion of CombiRx. We particularly were interested in the variability in time to site initiation between academic centers and private practice sites. RESULTS: Physicians who were directly involved in the medical care of patients with RRMS were the primary source of patients recruited to CombiRx. A flexible study design that allowed for rescreening of the initial screen failures after a period of time was useful due to the relapsing/remitting course of the disease. Academic centers took longer to implement the trial than the private practice centers, but once sites were approved for enrollment, there was no important difference in the number of participants enrolled. LIMITATIONS: The CombiRx trial was conducted during a period when multiple new medications were being tested, thus affecting the pace of recruitment and limiting ability to generalize our experiences. However, the lessons we learned about process are relevant. CONCLUSION: Participants can be enrolled successfully in a clinical trial for RRMS, but factors affecting the time to achieve the requirements needed to start screening can be unpredictable and problematic. Prospective planning by the sponsors and investigators, use of central institutional review boards (IRBs), master trial agreements and secure remote desktop access to the trial database may expedite trial implementation and participant recruitment. A good scientific research question with flexible study design and active involvement of the clinicians are important factors driving recruitment. Clinical trials can be implemented successfully both in private practices and at academic centers, a consideration when selecting sites.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Estudos Multicêntricos como Assunto/métodos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Seleção de Pacientes , Peptídeos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Método Duplo-Cego , Quimioterapia Combinada , Acetato de Glatiramer , Humanos , Interferon beta-1aRESUMO
Background: Health disparities in adult-onset multiple sclerosis have been identified in the Black/African American (AA) population. A higher relapse rate has been suggested in Black/AA patients with pediatric-onset MS (POMS), but little work explores healthcare utilization and social determinants of health (SDOH). Objective: To evaluate racial, ethnic, and socioeconomic disparities in POMS outcomes. Methods: Retrospective chart review identified 31 eligible patients diagnosed with POMS at Children's of Alabama between 2013 and 2023. Demographics, outcomes, and healthcare utilization over 2 years from diagnosis were collected. Patient addresses were connected to SDOH measures from the US Census. Bivariate analysis was performed using Fisher's Exact Test, Wilcoxin Test, and 2-sided t-test. Results: Black/AA children had a higher Expanded Disability Status Scale (EDSS) at first presentation (p = 0.0276) and were more likely to initiate fingolimod vs. glatiramer acetate (p = 0.0464). Living further from Children's of Alabama was associated with a higher most recent EDSS (p = 0.0301) and fewer neurology appointments (p = 0.0167). Families living in more socioeconomically deprived census tracts had significantly more hospital admissions. Conclusion: Black/AA POMS patients had a more severe initial presentation and were started on higher efficacy medication. We identified disparities in EDSS and healthcare utilization based on SDOH data linked to a child's home address.
RESUMO
BACKGROUND: Pilot trials indicate that both a low glycemic load (GL) diet and calorie restriction (CR) can be implemented successfully in people with multiple sclerosis (pMS) and may improve MS symptoms and physical function, but large randomized clinical trials (RCTs) have not yet been conducted. The purpose of this study is to test these interventions alone and in combination to determine their efficacy for improving clinical and patient reported outcomes (PROs) in pMS. METHODS: This 32-week, two-arm, RCT at two centers will randomly assign 100 adults with relapsing-remitting or secondary progressive MS to a low GL diet (nâ¯=â¯50) or a standard GL diet (nâ¯=â¯50). Both diet groups will complete two study phases: a eucaloric phase (16â¯weeks) and a CR phase (16â¯weeks). Groceries for the study meal plans will be delivered to participants' homes weekly. The primary outcome is physical function, measured by timed 25-ft walk test. Secondary outcomes are pain, fatigue, mood, and anxiety. DISCUSSION: This will be the most rigorous intervention trial to date of a low GL diet and CR in adults with MS, and among the first to assess the impact of intentional weight loss on MS symptoms. Results will provide valuable insight for recommending dietary change, weight loss, or both to adults with MS. These non-drug interventions pose few risks and have potential to yield significant improvements in MS symptoms. TRIAL REGISTRATION ID: NCT05327322.