RESUMO
BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (â¼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , BiomarcadoresRESUMO
OBJECTIVE: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. DESIGN: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. SETTING: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. PARTICIPANTS: Alzheimer's disease patients with clinically significant apathy. MEASUREMENTS: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). RESULTS: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. CONCLUSION: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.
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Doença de Alzheimer , Apatia , Demência , Metilfenidato , Humanos , Masculino , Idoso , Feminino , Doença de Alzheimer/psicologia , Metilfenidato/efeitos adversos , Atividades Cotidianas , Demência/tratamento farmacológico , Inibidores da Colinesterase/farmacologiaRESUMO
BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. METHODS: In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4-6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. DISCUSSION: Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. TRIAL REGISTRATION: The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).
Assuntos
Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/psicologia , Estimulação Magnética Transcraniana/métodos , Depressão/terapia , Qualidade de Vida , Córtex Pré-Frontal/fisiologia , Biomarcadores , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: This study was undertaken to evaluate the efficacy of vagus nerve stimulation (VNS) over time, and to determine which patient groups derive the most benefit. METHODS: Long-term outcomes are reported in 436 epilepsy patients from a VNS quality registry (52.8% adults, 47.2% children), with a median follow-up of 75 months. Patients were stratified according to evolution of response into constant responders, fluctuating responders, and nonresponders. The effect was evaluated at 6, 12, 24, 36, and 60 months. Multivariate regression analysis was used to identify predictors of response. RESULTS: The cumulative probability of ≥50% seizure reduction was 60%; however, 15% of patients showed a fluctuating course. Of those becoming responders, 89.5% (230/257) did so within 2 years. A steady increase in effect was observed among constant responders, with 48.7% (19/39) of those becoming seizure-free and 29.3% (39/133) with ≥75% seizure reduction achieving these effects within 2-5 years. Some effect (25%-<50%) at 6 months was a positive predictor of becoming a responder (odds ratio [OR] = 10.18, p < .0001) and having ≥75% reduction at 2 years (OR = 3.34, p = .03). Patients without intellectual disability had ORs of 3.34 and 3.11 of having ≥75% reduction at 2 and 5 years, respectively, and an OR of 6.22 of being seizure-free at last observation. Patients with unchanged antiseizure medication over the observation period showed better responder rates at 2 (63.0% vs. 43.1%, p = .002) and 5 years (63.4% vs. 46.3%, p = .031) than patients whose antiseizure medication was modified. Responder rates were higher for posttraumatic (70.6%, p = .048) and poststroke epilepsies (75.0%, p = .05) than other etiologies (46.5%). SIGNIFICANCE: Our data indicate that the effect of VNS increases over time and that there are important clinical decision points at 6 and 24 months for evaluating and adjusting the treatment. There should be better selection of candidates, as certain patient groups and epilepsy etiologies respond more favorably.
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Epilepsia Resistente a Medicamentos , Epilepsia , Estimulação do Nervo Vago , Adulto , Criança , Epilepsia Resistente a Medicamentos/terapia , Epilepsia/tratamento farmacológico , Humanos , Estudos Retrospectivos , Convulsões , Resultado do Tratamento , Nervo Vago/fisiologia , Estimulação do Nervo Vago/efeitos adversosRESUMO
OBJECTIVE: To investigate the associations between clinical, procedural, and radiographic factors and outcomes of steroid hip injections, including long-term and immediate pain reduction, time to arthroplasty, time to reinjection, and the total number of injections. MATERIALS AND METHODS: All intra-articular anesthetic and steroid injections of the hip under fluoroscopic guidance between January 2014 and March 2016 were retrospectively reviewed. Hip radiographs were scored using the Kellgren-Lawrence (KL) and Osteoarthritis Research Society International (OARSI) scores. Immediate pain relief and response were evaluated using a change in visual analog scale and OMERACT-OARSI criteria respectively. Long-term pain relief was evaluated at 27 months after injection by reviewing the medical records. Correlation between patient characteristics, procedural variations, and radiographic factors with injection outcomes was analyzed by using linear and logistic regression models. RESULTS: Of 361 injections, 79.8% showed an immediate pain response and 32.7% had subjective long-term pain relief (> 2 months). There was no significant correlation between immediate pain relief and response with long-term pain relief and other outcomes. Older age and higher KL score, OARSI-central joint space narrowing (JSN), and inferior acetabular osteophyte were correlated with long-term pain relief (p = 0.010.03). Higher KL and OARSI grades, particularly JSN, were significantly correlated with increased immediate pain relief and total number of injections but decreased time to arthroplasty. Baseline pain positively correlated with immediate pain response (p < 0.001). CONCLUSIONS: Older patients with higher grades of radiographic OA and high baseline pain were good candidates for steroid injections, particularly for those patients awaiting hip arthroplasty.
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Osteoartrite do Quadril , Corticosteroides/uso terapêutico , Idoso , Humanos , Injeções Intra-Articulares , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/tratamento farmacológico , Medição da Dor , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive vs active chronic infection. Interferon alfa may convert hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. METHODS: Hepatitis B surface proteins were measured before and during peginterferon alfa-2a therapy in serum from 127 Asian patients with HBeAg-positive CHB. Sustained response was defined as HBeAg seroconversion 24 weeks post-treatment. RESULTS: Mean total HBs levels were significantly lower in responders vs nonresponders at all time points (P < .05) and decreased steadily during the initial 24 weeks treatment (by 1.16 vs 0.86 ng/mL in responders/nonresponders respectively) with unchanged relative proportions. Genotype B had a two-fold higher proportion of LHBs than genotype C (13% vs 6%). HBV DNA, HBeAg, HBsAg and HBs protein levels predicted response equally well but not optimally (area under the receiver operating characteristic curve values >0.70). CONCLUSIONS: Hepatitis B surface protein levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa-2a therapy in HBeAg-positive patients.
Assuntos
Antígenos E da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Antígenos de Superfície da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Proteínas de Membrana , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort.Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model.Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0-51.4) were included. Median disease duration was 4.3 years (IQR 2.0-9.0) and follow-up 1.27 years (IQR 0.33-4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years.Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment.
Assuntos
Adalimumab/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Substituição de Medicamentos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab/efeitos adversos , Adulto , Fatores Etários , Proteína C-Reativa/metabolismo , Colectomia , Colite Ulcerativa/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Suécia , Fatores de Tempo , Falha de Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversosRESUMO
OBJECTIVE: To identify factors predicting response (2-hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult-to-treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed. BACKGROUND: Knowledge of factors associated with a positive or negative response to acute treatment would be useful to practitioners prescribing acute treatments for migraine. Additionally, practitioners and patients would benefit from understanding the efficacy of lasmiditan specifically in subgroups of patients with migraine disease characteristics and migraine attack characteristics historically associated with decreased pain threshold, reduced efficacy of acute treatment, or increased burden of migraine. METHODS: Pooled analyses were completed from 2 Phase 3 double-blind clinical trials, SPARTAN and SAMURAI. Data from baseline to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to assess efficacy based on patient characteristics, migraine disease characteristics, and migraine attack characteristics. A total of 3981 patients comprising the intent-to-treat population were treated with placebo (N = 1130), lasmiditan 50 mg (N = 598), lasmiditan 100 mg (N = 1133), or lasmiditan 200 mg (N = 1120). Data were analyzed for the following efficacy measures at 2 hours: headache pain freedom and most bothersome symptom freedom. RESULTS: None of the analyzed subgroups based on individual patient characteristics, migraine disease characteristics, or migraine attack characteristics predicted headache pain freedom or most bothersome symptom freedom response at 2 hours following lasmiditan treatment (interaction P ≥ .1). For the difficult-to-treat patient/migraine disease characteristics subgroups (defined as those with ≥24 headache days in the past 3 months, duration of migraine history ≥20 years, severe disability [Migraine Disability Assessment score ≥21], obesity [≥30 kg/m2 ], and history of psychiatric disorder), single doses of lasmiditan (100 or 200 mg) were significantly more effective than placebo (P ≤ .002) in achieving both endpoints. Headache pain freedom response rates for higher doses of lasmiditan were numerically greater than for lower doses of lasmiditan. For the difficult-to-treat migraine attack subgroups, patients with severe headache, co-existent nausea at the time of treatment, or who delayed treatment for ≥2 hours from the time of headache onset, both endpoint response rates after lasmiditan 100 or 200 mg were significantly greater than after placebo. Among those who delayed treatment for ≥4 hours from the time of headache onset, headache pain freedom response rates for the 200 mg dose of lasmiditan met statistical significance vs placebo (32.4% vs 15.9%; odds ratio = 2.7 [1.17, 6.07]; P = .018). While the predictors of response interaction test showed similar efficacy of lasmiditan vs placebo across subgroups defined by baseline functional disability (mild, moderate, or needs complete bed rest) at the time of treatment, analyses of lasmiditan efficacy within the subgroup "needs complete bed rest" appeared to show less efficacy (eg, in the 200 mg vs placebo group, 25.9% vs 18.5%; odds ratio = 1.56 [0.96, 2.53]; P = .070). CONCLUSIONS: Efficacy of lasmiditan 200 and 100 mg for headache pain freedom and most bothersome symptom freedom at 2 hours post-treatment was generally not influenced by the individual patient characteristics, migraine disease history, or migraine attack characteristics that were analyzed. In the analyses of difficult-to-treat subgroups, patients receiving lasmiditan achieved greater responses (2-hour headache pain freedom and most bothersome symptom freedom) vs placebo recipients.
Assuntos
Benzamidas/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Piperidinas/farmacologia , Piridinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Adolescente , Adulto , Idoso , Benzamidas/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/administração & dosagem , Fatores de Tempo , Adulto Jovem , Receptor 5-HT1F de SerotoninaRESUMO
RATIONALE: Reslizumab is a humanized anti-IL-5 monoclonal antibody used as add-on maintenance treatment for patients with uncontrolled eosinophilic asthma. OBJECTIVES: To predict response and nonresponse to intravenous reslizumab at 52 weeks with an algorithm we developed based on clinical indicators from pivotal clinical trials. METHODS: Patients aged 18 years and older who met Global Initiative for Asthma 4 or 5 criteria and received intravenous reslizumab (n = 321) in two trials ( www.clinicaltrials.gov identifiers, NCT01287039 and NCT01285323) were selected as the data source. A mathematical model was constructed that was based on change from baseline to 16 weeks in Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores and FEV1, and number of clinical asthma exacerbations during the year before enrollment and in the first 16 weeks of treatment, and these measures were evaluated for their ability to predict the outcome at 52 weeks: responder, nonresponder, or indeterminate. MEASUREMENTS AND MAIN RESULTS: The algorithm predicted that 276 patients would be classified as responders; in 248 (89.9%), the prediction was correct. In comparison, 26 patients were predicted to be nonresponders; 50.0% of these predictions were correct. Nineteen patients were classified as indeterminate. The algorithm had 95.4-95.5% sensitivity and 40.6-54.1% specificity. Jackknife and cross-study validation confirmed the robustness of the algorithm. CONCLUSIONS: Our algorithm enabled prediction at 16 weeks of treatment of the response to intravenous reslizumab treatment at 52 weeks, but it was not suitable for predicting nonresponse. A positive score at 16 weeks should encourage continued treatment, and a negative score should prompt close monitoring to determine whether discontinuation is warranted.
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Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Regras de Decisão Clínica , Eosinofilia Pulmonar/tratamento farmacológico , Adulto , Algoritmos , Humanos , Modelos Teóricos , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
BACKGROUND: Synchronized transcranial magnetic stimulation (sTMS) is a new modality to reduce symptoms of major depressive disorder (MDD). sTMS uses rotating neodymium magnets to deliver low-field stimulation matched to the individual alpha frequency (IAF). A previous multisite study showed that sTMS significantly reduced MDD symptoms in the per-protocol sample. To this end, we evaluated clinical features associated with optimal sTMS outcomes. METHODS: Using the per-protocol sample (n = 120) from the parent sham-controlled trial, we performed univariate and stepwise linear regression to identify predictors of response after 6 weeks of sTMS. A subsample (n = 83) that entered a 4-week open/active continuation phase also was examined. Candidate variables included age, sex, comorbid anxiety, number of failed antidepressants in the current depressive episode, MDD severity (17-item Hamilton Depression Rating Scale; HAMD17), anxiety symptom severity (HAMD17 anxiety/somatization factor), and IAF. RESULTS: We found that greater baseline depressive (p < 0.001) and anxiety (p < 0.001) symptom severity were associated with better response to active sTMS, whereas fewer failed antidepressant trials predicted superior response to sham (p < 0.001). MDD severity and antidepressant resistance predicted outcomes in open/active phase sTMS; lower IAF predicted poorer response in participants who received 10 weeks of active sTMS (p = 0.001). CONCLUSIONS: Participants with greater severity of depression and higher anxiety had superior responses to active sTMS, whereas treatment naïve individuals exhibited a greater response to sham. These results lend support to the primary efficacy findings, and support further investigation of sTMS as a therapeutic noninvasive brain stimulation modality.
Assuntos
Transtorno Depressivo Maior/terapia , Estimulação Magnética Transcraniana/métodos , Adulto , Idoso , Antidepressivos/farmacologia , Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/terapia , Comorbidade , Depressão/terapia , Método Duplo-Cego , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To investigate efficacy, safety and survival of belimumab and to identify predictors of drug response and drug discontinuation in patients with active SLE in clinical practice. PATIENTS AND METHODS: Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa (Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months. SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features and comorbidities were included in the univariate and multivariate analysis. Adverse events were recorded at each visit. Statistics was performed using the SPSS software. RESULTS: We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifestations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month response were SLEDAI-2K ≥ 10 (OR 40.46, p = 0.001) and polyarthritis (OR 12.64, p = 0.001) and of 24-month response were SLEDAI-2K ≥ 10 (OR 15.97, p = 0.008), polyarthritis (OR 32.36, p = 0.006), and prednisone ≥7.5 mg/day (OR 9.94, p = 0.026). We observed a low rate of severe adverse events. Fifty-eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors associated with drug discontinuation were found. CONCLUSION: Belimumab is effective and safe when used in clinical practice setting.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adolescente , Adulto , Biomarcadores Farmacológicos/metabolismo , Criança , Estudos de Coortes , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/mortalidade , Grupos Populacionais , Estudos Prospectivos , Análise de Sobrevida , Suspensão de Tratamento , Adulto JovemRESUMO
OBJECTIVES: Real world data regarding clinical response to ustekinumab in Crohn's disease is lacking. We report our experience of ustekinumab use using a novel subcutaneous (SC) induction strategy and aim to identify predictors of response. MATERIALS AND METHODS: A retrospective, observational study of compassionate ustekinumab use in Crohn's disease was conducted with the use of a standard or high dose SC induction protocol. Symptomatic response was assessed after 3 months (short-term), and if remaining on therapy, within 3-12 months (medium-term) and at least 12 months (long-term). Endoscopic or radiologic response was assessed when available. Survival analysis of time to failure (cessation of ustekinumab) and multivariate logistic regression to identify predictors of response were performed. RESULTS: Seventy-nine patients commenced ustekinumab, with six patients lost to follow-up and five asymptomatic at baseline. Symptomatic response was assessed in 68 patients; 56% (38) of patients had a short-term symptomatic response. Type of preceding anti-TNF response was the only significant predictor of short-term response, with primary non-response being a strong predictor. In the medium-term, symptomatic response occurred in 72% (30/42) of patients and endoscopic or radiologic response was achieved in 72% (26/36) of patients assessed. The median time to failure was 22 months. Maintenance dose escalation to 90 mg every 4 weeks was successful in three of 16 patients. CONCLUSIONS: Fifty-six percent of patients had short-term symptomatic response, with a history of primary non-response to prior anti-TNF therapy being a predictor of response. Dose escalation had only modest benefit.
Assuntos
Doença de Crohn/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab/administração & dosagem , Adolescente , Adulto , Canadá , Ensaios de Uso Compassivo , Relação Dose-Resposta a Droga , Endoscopia , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Indução de Remissão , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto JovemRESUMO
BACKGROUND: Intra-articular corticosteroid injections (IACI) are effective treatments for pain in knee osteoarthritis (KOA) but treatment response varies. There is uncertainty as to whether structural factors such as accurate placement of IACI affect outcome. We examined this question in a pragmatic observational study, using ultrasound (US) to verify accuracy of IACI. METHODS: 105 subjects with KOA (mean age 63.1 years, 59% female) routinely referred for IACI underwent assessment of demographic factors, x-ray and US of the knee before aspiration and IACI (based on clinical landmarks) with 40 mg triamcinolone acetonide with lignocaine plus a small amount of atmospheric air by an independent physician. US demonstration of intra-articular mobile air, i.e. a positive air arthrosonogram, was used to determine accurate placement of injection. Both patients and injecting physicians were blind to the US findings. Pain at baseline, three and nine weeks post injection was assessed using the 500 mm WOMAC pain subscale and response defined as ≥ 40% reduction in pain from baseline. Inter-observer reliability of air-arthrosonogram assessment was good: κ 0.79 (three raters). RESULTS: Sixty-three subjects (60.6%) were responders at three weeks and 43 (45.7%) at nine weeks. Seventy-four subjects (70.5%) had a positive arthrosonogram. A positive air arthrosonogram did not associate with a higher rate of response to treatment (p 0.389 at three weeks, p 0.365 at nine weeks). There was no difference in US effusion depth, power Doppler signal or radiographic grade between responders and non-responders to the injection, but female gender associated with response at 3 weeks and previous injection with non-response at 9 weeks. CONCLUSIONS: Accurate intra-articular injection of corticosteroid results did not result in superior outcome in terms of pain compared to inaccurate injection in symptomatic knee OA.
Assuntos
Anestésicos Locais/administração & dosagem , Glucocorticoides/administração & dosagem , Lidocaína/administração & dosagem , Osteoartrite do Joelho/tratamento farmacológico , Manejo da Dor/métodos , Triancinolona Acetonida/administração & dosagem , Idoso , Pontos de Referência Anatômicos , Anestésicos Locais/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Injeções Intra-Articulares/métodos , Articulação do Joelho/diagnóstico por imagem , Lidocaína/uso terapêutico , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Medição da Dor , Estudos Prospectivos , Radiografia , Reprodutibilidade dos Testes , Resultado do Tratamento , Triancinolona Acetonida/uso terapêutico , Ultrassonografia Doppler , Ultrassonografia de IntervençãoRESUMO
OBJECTIVE: To create a tool to predict probability of remission and low disease activity (LDA) in patients with RA being considered for anti-TNF treatment in clinical practice. METHODS: We analysed data from GO-MORE, an open-label, multinational, prospective study in biologic-naïve patients with active RA (DAS28-ESR ⩾3.2) despite DMARD therapy. Patients received 50 mg s.c. golimumab (GLM) once monthly for 6 months. In secondary analyses, regression models were used to determine the best set of baseline factors to predict remission (DAS28-ESR <2.6) at month 6 and LDA (DAS28-ESR ⩽3.2) at month 1. RESULTS: In 3280 efficacy-evaluable patients, of 12 factors included in initial regression models predicting remission or LDA, six were retained in final multivariable models. Greater likelihood of LDA and remission was associated with being male; younger age; lower HAQ, ESR (or CRP) and tender joint count (or swollen joint count) scores; and absence of comorbidities. In models predicting 1-, 3- and 6-month LDA or remission, area under the receiver operating curve was 0.648-0.809 (R(2) = 0.0397-0.1078). The models also predicted 6-month HAQ and EuroQoL-5-dimension scores. A series of matrices were developed to easily show predicted rates of remission and LDA. CONCLUSION: A matrix tool was developed to show predicted GLM treatment outcomes in patients with RA, based on a combination of six baseline characteristics. The tool could help provide practical guidance in selection of candidates for anti-TNF therapy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Análise de Regressão , Indução de Remissão , Resultado do TratamentoRESUMO
OBJECTIVE: Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine's ability to decrease symptoms of depression. METHODS: Thirty-six patients with anxious (n = 21) and non-anxious (n = 15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 min. Post-hoc analyses compared changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non-anxious depressed patients with bipolar disorder through 14 days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7. RESULTS: A linear mixed model revealed a significant effect of anxiety group on the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p < 0.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine. The drug-by-anxiety interactions were not significant (all p > 0.28). CONCLUSIONS: Both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine's novel role in the treatment of anxious bipolar depression.
Assuntos
Afeto/efeitos dos fármacos , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Depressão/tratamento farmacológico , Depressão/psicologia , Ketamina/administração & dosagem , Adulto , Transtornos de Ansiedade , Estudos Cross-Over , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Infusões Intravenosas , Carbonato de Lítio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ácido Valproico/administração & dosagemRESUMO
OBJECTIVES: Self-reported sleep disturbance (SD) is a distressing symptom in patients with advanced cancer. There are limited data on the treatment of SD and predictors to response of SD to outpatient supportive care clinic (OPC) consultation. The aims of our study was to determine the frequency, intensity, and correlates of SD as assessed with the Edmonton Symptom Assessment System (ESAS) sleep item at the time of initial consultation and identify the predictors of improvement in SD at follow-up. METHODS: We reviewed the records of consecutive patients with advanced cancer presenting to the OPC. ESAS scores were obtained at the initial and subsequent visits between January 2008 and February 2010. All patients underwent screening for SD (0-10 scale: 0 = best sleep, presence of SD defined as ≥ 3) and interdisciplinary assessment and treatment, including drug review, counseling, sleep hygiene review, and drug therapy. A response was defined as a 1-point improvement at the follow-up visit on the Edmonton Symptom Assessment Scale (ESAS) sleep item score. Baseline patient characteristics, medication use, and ESAS scores were analyzed to determine their association with response. RESULTS: The median age was 58 years, and 53% of patients were men. The most common cancer type was head and neck or lung (36%). Of the 442 patients, 330 had baseline SD (score ≥ 3/10, 75%). Median and mean (standard deviation) baseline SD scores were 5 and 5.1 (2.9). The multivariable regression model found the intensity of baseline ESAS sleep item scores to be associated with baseline sedative use, baseline ESAS pain scores, baseline ESAS fatigue scores, baseline ESAS feeling of well-being scores, and sedative use (R 2 = 0.22). Sleep disturbance response at first follow-up was seen in 196 of 330 patients (59%). Moderate to high SD score and anxiety at initial visit with odds ratios (OR) of 2.53 (p = 0.0007) and 1.59 (p = 0.048), respectively, were associated with a response. SIGNIFICANCE OF RESULTS: Both the frequency and severity of SD were high. Response to supportive care consultation was substantial. The severity of SD and anxiety at the initial visit predicted a response at first follow-up. Further research is needed.
Assuntos
Neoplasias/complicações , Cuidados Paliativos , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: The pool of HCV genotype 1 patients likely to be cured by peg-interferon and ribavirin remains to be quantified. METHODS: In 1045 patients treated with peg-interferon and ribavirin, two therapeutic strategies were confronted: the first one evaluated only baseline variables associated with sustained virological response (SVR), and the second one included the rapid virologic response (RVR) in addition to baseline predictors. An 80% SVR rate was the threshold to retain a strategy as clinically relevant. RESULTS: Overall, 414 patients (39.6%) attained SVR. In the first strategy, the hierarchy of features independently associated with SVR was IL28B CC genotype (OR 5.082; CI 3.637-7.101), low (<400,000 IU) viremia (OR 2.907; CI 2.111-4.004), F0-F2 fibrosis (OR 1.631; CI 1.122-2.372) and type 2 diabetes (OR 0.528; CI 0.286-0.972). In the alternative strategy, SVR was associated with RVR (OR 6.273; CI 4.274-9.208), IL28B CC genotype (OR 3.306; CI 2.301-4.751), low viremia (OR 2.175; CI 1.542-3.070), and F0-F2 fibrosis (OR 1.506; CI 1.012-2.242). Combining the favorable baseline variables, the rates of SVR ranged from 42.4% to 83.3%, but only 66 patients (6.3%, overall) with all predictors could be anticipated to reach the >80% SVR threshold. Only 26.6% of no-RVR patients attained SVR. Among the 255 RVR patients, the likelihood of SVR was 61.8% in those with unfavorable predictors, 80% in the presence of a single predictor, and 100% when both predictors were present. By using this model, 200 patients (19.1%) were predicted to have an 80% chance of being cured with dual therapy. CONCLUSIONS: A consistent subset of naïve HCV-1 patients, identified by some baseline characteristics and RVR, may benefit from dual treatment with peg-interferon and ribavirin.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/classificação , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Idoso , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagemRESUMO
OBJECTIVE: The objective of this study was to identify predictors of response and remission to tocilizumab (TCZ) in RA patients seen in daily routine clinical practice. METHODS: The efficacy of TCZ was evaluated after 12 and 24 weeks of treatment by the European League Against Rheumatism (EULAR) response criteria. Regression analysis was performed to study the association between remission or EULAR response and the following characteristics: gender, age, current smokers, prior cardiovascular disease (CVD), 28-joint disease activity score (DAS28), CRP, RF or ACPA positivity, combination therapy with DMARDs and TCZ as the first biological therapy or after failure of at least one biological therapy. RESULTS: In total, 204 patients were included with a mean DAS28 score of 5.14. EULAR response and remission were obtained in 86.1% and 40% of patients, respectively, at week 24. In multiple regression analysis, a high baseline CRP level [odds ratio (OR) 4.454 (95% CI 1.446, 13.726)] was significantly associated with EULAR response at week 24 and, inversely, age >55 years [OR 0.285 (95% CI 0.086, 0.950)] and prior CVD [OR 0.305 (95% CI 0.113, 0.825)] were significantly associated with lower EULAR response at week 24. Older age was also associated with less remission at week 24 [OR 0.948 (95% CI 0.920, 0.978)]. No additional effectiveness was found when TCZ was used in combination with a DMARD or when patients were naive to biological agents. CONCLUSION: In daily practice we identified three predictors of a better response for TCZ therapy in RA: a younger age, a high baseline CRP level and no history of CVD.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Indução de Remissão , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: Depression and chronic low back pain (CLBP) are both frequent and commonly comorbid in older adults seeking primary care. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine may be effective in treating comorbid depression and CLBP. For patients with comorbid depression and CLBP, our goal was to identify "easy-to-use" early clinical variables associated with response to 6 weeks of low-dose venlafaxine pharmacotherapy that could be used to construct a clinically useful predictive model in future studies. METHODS: We report data from the first 140 patients completing phase 1 of the Addressing Depression and Pain Together clinical trial. Patients aged ≥60 with concurrent depression and CLBP received 6 weeks of open-label venlafaxine 150 mg/day and supportive management. Using univariate and multivariate methods, we examined a variety of clinical predictors and their association with response to both depression and CLBP; change in depression; and change in pain scores at 6 weeks. RESULTS: About 26.4% of patients responded for both depression and pain with venlafaxine. Early improvement in pain at 2 weeks predicted improved response rates (P = 0.027). Similarly, positive changes in depression and pain at 2 weeks independently predicted continued improvement at 6 weeks in depression and pain, respectively (P < 0.001). CONCLUSIONS: An important minority of patients benefitted from 6 weeks of venlafaxine 150 mg/day. Early improvement in depression and pain at 2 weeks may predict continued improvement at week 6. Future studies must examine whether patients who have a poor initial response may benefit from increasing the SNRI dose, switching, or augmenting with other treatments after 2 weeks of pharmacotherapy.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Cicloexanóis/uso terapêutico , Depressão/tratamento farmacológico , Idoso , Dor Crônica/complicações , Dor Crônica/tratamento farmacológico , Dor Crônica/psicologia , Depressão/complicações , Feminino , Humanos , Dor Lombar/complicações , Dor Lombar/tratamento farmacológico , Dor Lombar/psicologia , Masculino , Resultado do Tratamento , Cloridrato de VenlafaxinaRESUMO
AIMS: Researchers report varying levels of cognitive flexibility and theory of mind (ToM) deficiencies in adolescents with obsessive-compulsive disorder (OCD). This research set out to investigate the impact of these variables on the disorder's outcomes. METHOD: The study involved 39 adolescents with OCD and 40 healthy controls. We assessed the case group at the initial visit to the outpatient clinic and again at the end of the first year of treatment. The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was applied to assess OCD symptom distribution and severity. The Reading the Mind in the Eyes of Children Test (RME-CT) was applied to evaluate ToM skills, and the Cognitive Flexibility Scale (CFS) was employed to evaluate cognitive flexibility levels. RESULTS: Baseline RME-CT and CFS scores were significantly lower in adolescents with OCD compared to the control group (p = 0.002 p = 0.001, respectively). At the end of the 1-year follow-up, RME-CT and CFS scores increased significantly in the adolescents with OCD (p < 0.001, p = 0.003, respectively). A significant negative correlation was observed between the initial RME-CT scores and the Y-BOCS scores at the end of the 1-year follow-up (p < 0.001). The initial RME-CT score had a significant negative predictive effect on the subsequent severity of OCD (ß = -0.711, p < 0.001). CONCLUSIONS: The research revealed poorer long-term prognoses for OCD in adolescents who exhibit low ToM skills. In conclusion, the results indicate that ToM skills may serve as a predictive factor for long-term treatment outcomes among adolescents diagnosed with OCD.