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2.
Rheumatology (Oxford) ; 59(2): 344-360, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31325311

RESUMO

OBJECTIVES: The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. METHODS: We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. RESULTS: Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. CONCLUSION: Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.

3.
Mult Scler ; : 1352458519887343, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31686590

RESUMO

BACKGROUND: There is an unmet need for precise methods estimating disease prognosis in multiple sclerosis (MS). OBJECTIVE: Using advanced statistical modeling, we assessed the prognostic value of various clinical measures for disability progression. METHODS: Advanced models to assess baseline prognostic factors for disability progression over 2 years were applied to a pooled sample of patients from placebo arms in four different phase III clinical trials. least absolute shrinkage and selection operator (LASSO) and ridge regression, elastic nets, support vector machines, and unconditional and conditional random forests were applied to model time to clinical disability progression confirmed at 24 weeks. Sensitivity analyses for different definitions of a combined endpoint were carried out, and bootstrap was used to assess prediction model performance. RESULTS: A total of 1582 patients were included, of which 434 (27.4%) had disability progression in a combined endpoint over 2 years. Overall model discrimination performance was relatively poor (all C-indices ⩽ 0.65) across all models and across different definitions of progression. CONCLUSION: Inconsistency of prognostic factor importance ranking confirmed the relatively poor prediction ability of baseline factors in modeling disease progression in MS. Our findings underline the importance to explore alternative predictors as well as alternative definitions of commonly used endpoints.

4.
Mult Scler Relat Disord ; 36: 101430, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31610404

RESUMO

OBJECTIVE: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients. METHODS: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring). RESULTS: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis. INTERPRETATION: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.

5.
Mult Scler ; : 1352458519872889, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573386

RESUMO

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS. METHODS: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. RESULTS: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose. CONCLUSION: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

6.
Ann Rheum Dis ; 78(10): 1357-1362, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31296501

RESUMO

OBJECTIVE: To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA). METHODS: The clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples. RESULTS: The MS score ranges from -8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥-2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample. CONCLUSION: The MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.

7.
Mol Hum Reprod ; 25(9): 527-537, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174207

RESUMO

In ART, embryo quality evaluation is routinely based on morphological criteria. We previously demonstrated that the mitochondrial DNA (mtDNA)/genomic DNA (gDNA) ratio in culture medium was significantly associated with embryo quality and viability potential. The purpose of this prospective, blinded, multi-centric study was to validate the use of mtDNA/gDNA ratio in Day 3 spent medium as a predictor of human embryo developmental competence. The mtDNA/gDNA ratio was assessed in Day 3 culture media (n=484) of embryos from 143 patients by quantitative PCR. A mixed effect logistic regression model was applied. We found that mtDNA/gDNA ratio in Day 3 culture medium combined with embryo morphology improves the prediction upon blastulation compared to morphology alone (P < 0.0001), independent of patient and cycle characteristics. With regard to routine use in clinics, we evaluated the ability of the novel, combined grading score to improve selection of developmentally competent embryos of a single cohort. Including embryos from 44 patients, the sensibility and specificity of the scoring system based on Day 3 morphological stage were 92% and 13%, respectively. Integration with the culture medium mtDNA/gDNA ratio increased the performance of the method (sensibility: 95%; specificity: 65%). The results of this study suggest the possibility of carrying out a non-invasive evaluation of embryonic mtDNA content through the culture medium. When combined with embryo morphology, it has the potential to help embryologists rank embryos and choose which embryo(s) has the greater development potential, and thus should be transferred on Day 3, among sibling embryos with the same morphological grade.

8.
BMC Med ; 17(1): 113, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31208412

RESUMO

BACKGROUND: Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients' characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy. METHODS: We show here a previously published statistical method, aimed at identifying patients' profiles associated to larger treatment benefits applied to three identical randomized clinical trials in multiple sclerosis, testing laquinimod vs placebo (ALLEGRO, BRAVO, and CONCERTO). We identified on the ALLEGRO patients' specific linear combinations of baseline variables, predicting heterogeneous response to treatment on disability progression. We choose the best score on the BRAVO, based on its ability to identify responders to treatment in this dataset. We finally got an external validation on the CONCERTO, testing on this new dataset the performance of the score in defining responders and non-responders. RESULTS: The best response score defined on the ALLEGRO and the BRAVO was a linear combination of age, sex, previous relapses, brain volume, and MRI lesion activity. Splitting patients into responders and non-responders according to the score distribution, in the ALLEGRO, the hazard ratio (HR) for disability progression of laquinimod vs placebo was 0.38 for responders, HR = 1.31 for non-responders (interaction p = 0.0007). In the BRAVO, we had similar results: HR = 0.40 for responders and HR = 1.24 for non-responders (interaction p = 0.006). These findings were successfully replicated in the CONCERTO study, with HR = 0.44 for responders and HR=1.08 for non-responders (interaction p = 0.033). CONCLUSIONS: This study demonstrates the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice.


Assuntos
Esclerose Múltipla/terapia , Medicina de Precisão/métodos , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Adulto Jovem
9.
Mult Scler ; : 1352458519849513, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31144577

RESUMO

BACKGROUND: Stratified medicine methodologies based on subgroup analyses are often insufficiently powered. More powerful personalized medicine approaches are based on continuous scores. OBJECTIVE: We deployed a patient-specific continuous score predicting treatment response in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Data from two independent randomized controlled trials (RCTs) were used to build and validate an individual treatment response (ITR) score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. RESULTS: The ITR score for the combined treatment groups versus placebo detected differential clinical response in both RCTs. High responders in one RCT had a cross-validated ARR ratio of 0.29 (95% confidence interval (CI) = 0.13-0.55) versus 0.62 (95% CI = 0.47-0.83) for all other responders (heterogeneity p = 0.038) and were validated in the other RCT, with the corresponding ARR ratios of 0.31 (95% CI = 0.18-0.56) and 0.61 (95% CI = 0.47-0.79; heterogeneity p = 0.036). The strongest treatment effect modifiers were the Short Form-36 Physical Component Summary, age, Visual Function Test 2.5%, prior MS treatment and Expanded Disability Status Scale. CONCLUSION: Our modelling strategy detects and validates an ITR score and opens up avenues for building treatment response calculators that are also applicable in routine clinical practice.

10.
Ann Rheum Dis ; 78(8): 1025-1032, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31018962

RESUMO

BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

11.
Lancet Child Adolesc Health ; 3(4): 255-263, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30819662

RESUMO

BACKGROUND: To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status. METHODS: In this multinational, cross-sectional, observational cohort study, we asked international paediatric rheumatologists from specialised centres to enrol children with a diagnosis of juvenile idiopathic arthritis, according to International League of Associations for Rheumatology criteria, who were seen consecutively for a period of 6 months. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. We qualitatively compared the collected data across eight geographical areas, and we explored an association between disease activity and damage and a country's gross domestic product (GDP) with a multiple logistic regression analysis. FINDINGS: Between April 4, 2011, and Nov 21, 2016, 9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. Systemic arthritis (125 [33·0%] of 379 patients) and enthesitis-related arthritis (113 [29·8%] of 379) were more common in southeast Asia, whereas oligoarthritis was more prevalent in southern Europe (1360 [56·7%] of 2400) and rheumatoid factor-negative polyarthritis was more frequent in North America (165 [31·5%] of 523) than in the other areas. Prevalence of uveitis was highest in northern Europe (161 [19·1%] of 845 patients) and southern Europe (450 [18·8%] of 2400) and lowest in Latin America (54 [6·4%] of 849), Africa and Middle East (71 [5·9%] of 1209), and southeast Asia (19 [5·0%] of 379). Median age at disease onset was lower in southern Europe (3·5 years, IQR 1·9-7·3) than in other regions. Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had greater disease activity and damage than those living in wealthier countries. Damage was associated with referral delay. INTERPRETATION: Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographical areas and wealth status of countries. The greater disease burden in lower-resource settings highlights the need for public health efforts aimed at improving equity in access to effective treatments and care for juvenile idiopathic arthritis. FUNDING: IRCCS Istituto Giannina Gaslini.

12.
Muscle Nerve ; 59(4): 426-430, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30677148

RESUMO

INTRODUCTION: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3. METHODS: Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module. RESULTS: The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0.45 in type 2, -0.23 in non-ambulant type 3 and -0.34 in ambulant type 3, p = 0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients. DISCUSSION: Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non-ambulant patients of different ages in conjunction with other functional scales. Muscle Nerve 59:426-430, 2019.


Assuntos
Atrofia Muscular Espinal/patologia , Atrofias Musculares Espinais da Infância/patologia , Extremidade Superior/patologia , Adolescente , Adulto , Algoritmos , Criança , Pré-Escolar , Progressão da Doença , Feminino , Nível de Saúde , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Caminhada , Adulto Jovem
13.
Rheumatology (Oxford) ; 58(7): 1196-1205, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30690571

RESUMO

OBJECTIVE: To develop a composite DAS for JDM and provide preliminary evidence of its validity. METHODS: The Juvenile DermatoMyositis Activity Index (JDMAI) is composed of four items: physician's global assessment of overall disease activity; parent's/child's global assessment of child's wellbeing; measurement of muscle strength; and assessment of skin disease activity. The score of the JDMAI is the arithmetic sum of the scores of each individual component. Six versions of the JDMAI were tested, which differed in the tools used to assess the third and fourth items. Validation procedures were conducted using three large multinational patient samples including a total of 627 patients. RESULTS: The JDMAI was found to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha = 0.58-0.89), fair responsiveness to clinically important change (standardized response mean = 0.82-3.12 among patients improved) and strong capacity to discriminate patients judged as being in the state of inactive disease or low, moderate or high disease activity by the physician (P < 0.001) or whose parents were satisfied or not satisfied with the course of their child's illness (P < 0.001). Overall, the six versions of the JDMAI showed similar metrological performances in validation analyses. CONCLUSION: The JDMAI was found to possess good measurement properties in a large population of patients with a wide range of disease activity, and is, therefore, suitable for use in both clinical and research settings. The final version of the JDMAI will be selected after its prospective validation.

14.
Neurol Sci ; 40(2): 319-326, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30430315

RESUMO

BACKGROUND AND AIMS: Monitoring the quality of acute ischemic stroke (AIS) management is increasingly important since patient outcome could be improved with better access to evidence-based treatments. In this scenario, the aim of our study was to identify thrombolysis rate, reasons for undertreatment, and factors associated with better outcome. METHODS: From January to December 2016, individuals diagnosed with AIS at the Policlinic San Martino Hospital in Genoa, Italy, were prospectively included. Severity of stroke, site of occlusion, rate and time related in-hospital management of systemic thrombolysis, and mechanical thrombectomy were recorded. Safety and clinical outcomes were compared between different subgroups. RESULTS: Of 459 AIS patients (57.3% females, mean age 78.1), 111 received i.v. thrombolysis (24.4%) and 50 received mechanical thrombectomy (10.9%). Apart from arrival behind the therapeutic window, which was the first limitation to thrombolysis, the main reason of undertreatment was minor stroke or stroke in rapid improvement. Baseline NIHSS ≥ 8 was associated with unfavorable clinical outcome (mRS > 2) (OR 20.1; 95% CI, 1.1-387.4, p = 0.047). Age older than 80 years (OR 5.0; 95% CI, 1.4-64.1, p = 0.01), baseline NIHSS ≥ 7 (OR 20.1; 95% CI, 1.1-387.4, p = 0.047), and symptomatic intracranial hemorrhage (OR 22.9; 95% CI, 2.0-254.2, p = 0.01) proved independently associated with mortality. CONCLUSIONS: i.v. thrombolysis and mechanical thrombectomy rate was higher than that of previous reports. Minor stroke or stroke in rapid improvement was a major reason for exclusion from thrombolysis of eligible patients. Higher NIHSS proved an independent predictor of unfavorable clinical outcome and death. Strategies to avoid in-hospital delays need to be enforced.


Assuntos
Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Trombólise Mecânica , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Terapia Trombolítica , Doença Aguda , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Monitorização Fisiológica , Prognóstico , Estudos Prospectivos , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Tempo para o Tratamento
15.
Lasers Med Sci ; 34(2): 431, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30350122

RESUMO

In the originally published article, the name of the first author was incorrectly labeled. Given name is Isabelle and family name is Fini Storchi.

16.
Mult Scler ; 25(9): 1263-1272, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30044207

RESUMO

BACKGROUND: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. OBJECTIVES: To identify prognostic factors for early switch after first therapy choice. METHODS: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. RESULTS: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). CONCLUSION: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

17.
Mult Scler ; 25(2): 217-223, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29154721

RESUMO

BACKGROUND: Baseline brain volume (BV) is predictive at a group level but is difficult to interpret at the single patient level. OBJECTIVE: To validate BV cutoffs able to identify clinically relevant atrophy in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: The expected normalized brain volume (NBV) for each patient was calculated using RRMS patients from two phase III clinical trials, applying a linear formula developed on the baseline variable of an independent data set. The difference between these expected NBV values and those actually observed was calculated and used to categorize the patients in the low-NBV, medium-NBV, and high-NBV groups. RESULTS: The 2-year probability of 3-month confirmed disability worsening was significantly associated with the NBV categorization ( p = 0.006), after adjusting for treatment effect. Taking the high-NBV group as a reference, the hazard ratios for the medium-NBV and low-NBV groups were 1.22 (95% confidence interval (CI): 0.85-1.76, p = 0.27) and 1.69 (95% CI: 1.11-2.57, p = 0.01), respectively. CONCLUSION: This study validates the use of BV cutoffs to identify clinically relevant atrophy in RRMS study by showing that the three groups classified according to the baseline NBV adjusted for the other prognostic variables have a significant prognostic impact on the risk of disability progression.


Assuntos
Encéfalo/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Adulto , Atrofia/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Valores de Referência
18.
Arthritis Res Ther ; 20(1): 285, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587248

RESUMO

BACKGROUND: The availability of methotrexate and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to accurately monitor the long-term safety/efficacy of these agents. This report aims to present the combined data coming from Pharmachild/PRINTO registry and the national registries from Germany (BiKeR) and Sweden. METHODS: Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESIs). For the Swedish register, AE data were not available. RESULTS: Data from a total of 15,284 patients were reported: 8274 (54%) from the Pharmachild registry and 3990 (26%) and 3020 (20%) from the German and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 versus 7.6 years) at JIA onset and shorter disease duration at last available visit (5.3 versus 6.1-6.8) when compared with the other registries. The most frequent JIA category was the rheumatoid factor-negative polyarthritis (range of 24.6-29.9%). Methotrexate (61-84%) and etanercept (24%-61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs), respectively. There was a wide variability in glucocorticoid use (16.7-42.1%). Serious AEs were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AEs (29.4-30.1%) followed by gastrointestinal disorders (11.5-19.6%). The most frequent ESIs were infections (75.3-89%). CONCLUSIONS: This article is the first attempt to present a very large sample of data on JIA patients from different national and international registries and represents the first proposal for data merging as the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA. REGISTRY REGISTRATION: The Pharmachild registry is registered at ClinicalTrials.gov ( NCT01399281 ) and at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) ( http://www.encepp.eu/encepp/viewResource.htm?id=19362 ). The BiKeR registry is registered at ENCePP ( http://www.encepp.eu/encepp/viewResource.htm?id=20591 ).


Assuntos
Artrite Juvenil/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Farmacovigilância , Sistema de Registros/estatística & dados numéricos , Medicamentos Sintéticos/uso terapêutico , Adolescente , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Juvenil/diagnóstico , Produtos Biológicos/efeitos adversos , Criança , Pré-Escolar , Monitoramento de Medicamentos , Etanercepte/efeitos adversos , Etanercepte/uso terapêutico , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Medicamentos Sintéticos/efeitos adversos , Resultado do Tratamento
19.
Ann Neurol ; 84(4): 621-625, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30179270

RESUMO

Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25-Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621-625.


Assuntos
Avaliação da Deficiência , Progressão da Doença , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/epidemiologia , Canadá/epidemiologia , Bases de Dados Factuais/tendências , Europa (Continente)/epidemiologia , Europa Oriental/epidemiologia , Humanos , Esclerose Múltipla/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Estados Unidos/epidemiologia , Teste de Caminhada/métodos , Teste de Caminhada/tendências
20.
Biol Blood Marrow Transplant ; 24(12): 2501-2508, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30041010

RESUMO

Disease relapse remains an unmet medical need for patients with Hodgkin lymphoma (HL) receiving an allogeneic hematopoietic cell transplantation (HCT). With the aim of identifying patients at high risk for post-transplant relapse, we retrospectively reviewed 41 HL patients who had received haploidentical (haplo) nonmyeloablative (NMA) HCT with high dose post-transplant cyclophosphamide (PT-Cy) for graft-versus-host (GVHD) prophylaxis. Primary refractory disease, relapse within 6 months from autologous stem cell transplantation, age, pretransplant chemotherapy, HCT comorbidity index (HCT-CI), sex mismatch, tumor burden and pretransplant fluorodeoxyglucose positron emission tomography (FDG-PET) status, assessed by Deauville score, were analyzed as variables influencing outcomes. All but 1 patient engrafted: median time to neutrophil and platelet recovery was 15 (interquartile range, 13 to 23) days and 19 (interquartile range, 12 to 28) days, respectively. Cumulative incidence of severe (grade III to IV) acute graft-versus-host disease (GVHD) and 3-year moderate-severe chronic GVHD was 2.4% and 11.8%, respectively. The 3-year overall (OS), progression free (PFS), and graft relapse-free survival (GRFS) were 75.6%, 43.9%, and 39%, respectively. On multivariate analysis, 3-year OS was significantly worse in patients with HCT-CI ≥3 (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.1 to 21.8; P = .03). Three-year relapse rate, 3-year PFS, and 3-year GRFS were significantly worse in patients with HCT-CI ≥3 (HR, 3.5; 95% CI, 1.3 to 9.3; P = .01; HR, 3.3; 95% CI, 1.2 to 9.0; P = .02; and HR, 4.2; 95% CI, 1.7 to 9.9; P = .001, respectively) and in patients with a Deauville score ≥4 on pretransplant FDG-PET (HR, 4.4; 95% CI, 1.6-12.4; P = .005, HR, 3.8; 95% CI, 1.5 to 9.7; P = .005; and 3.2; 95% CI, 1.3 to 7.9; P = .01, respectively). On univariate analysis, 3-year NRM was significantly worse only in patients with a HCT-CI ≥3 (HR, 17.6; 95% CI, 1.4 to 221.0). Among relapsed or refractory HL patients undergoing haplo NMA HCT with PT-Cy, pretransplant FDG-PET with a Deauville score ≥4 and HCT-CI ≥3 identified patients at high risk of relapse. Moreover, an HCT-CI ≥3 was associated with higher NRM and lower OS.


Assuntos
Ciclofosfamida/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/cirurgia , Imunossupressores/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Transplante Haploidêntico/métodos , Adulto , Comorbidade , Ciclofosfamida/farmacologia , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Humanos , Imunossupressores/farmacologia , Masculino , Recidiva Local de Neoplasia
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