Clinical activity after fingolimod cessation: Disease reactivation or rebound?

Background and purpose: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. Methods: Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. Results: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. Conclusions: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described

Segurança na mudança direta de natalizumabe para fingolimode em um grupo de pacientes com esclerose múltipla e positivos para JCV

To assess safety of the switch between natalizumab and fingolimod without a washout period. Methods Prospective data on 25 JCV positive patients who underwent this medication switch were collected and analyzed. Results After a median period of nine months from the medication switch, there were no safety issues to report. The patients had good disease control and no adverse events were reported. Conclusion Washout may not be necessary in daily practice when switching from natalizumab to fingolimod. Expertise on multiple sclerosis management, however, is essential for drug switching748650652Avaliar a segurança na mudança entre natalizumabe e fingolimode sem período de washout. Métodos Dados prospectivos de 25 pacientes positivos para vírus JC que tiveram sua medicação modificada foram coletados e analisados. Resultados Após uma mediana de nove meses da troca de medicação, não havia aspectos de segurança a relatar. Os pacientes estavam com bom controle da doença e não foram relatados eventos adversos. Conclusão Washout pode não ser necessário na prática diária para a mudança entre natalizumabe e fingolimode. No entanto, expertise no manejo de esclerose múltipla é essencial para esta troca entre medicaçõe

A real world experience with fingolimod in active RRMS patients naïve to second-line agents: a 2 years, intention-to-treat, observational, single center study

Fingolimod is approved by EMA as a second-line treatment for relapsing-remitting multiple sclerosis (RRMS). Experience with fingolimod in real life is still limited. Aim of our study was to report data on fingolimod effectiveness in a real life cohort of Italian active RRMS patients, naive to second-line agents, followed for 2 years. Fingolimod was a part of the patients' regular treatment and is produced by Novartis. We included all consecutive RRMS patients starting fingolimod at our center according to EMA criteria before January 1st 2013. Exclusion criteria were a previous treatment with natalizumab or an immunosuppressant therapy in the previous 12 months. All patients were clinically evaluated quarterly, and performed brain MRI yearly. Definition of "no evidence of disease activity" (NEDA-3): no relapses, no brain MRI activity and no 6-months confirmed worsening in EDSS score. We included 38 RRMS patients, 35 switched from first-line injectable therapies. Six patients were also previously treated with immunosuppressants (5 mitoxantrone, 1 cyclophosphamide). At 24th month 34 patients continued fingolimod treatment. Main adverse events were infections (18 %), liver-enzymes elevation (8 %), and leukopenia (8 %). After 12 and 24 months 79 and 63 % of patients were relapses-free. Fingolimod significantly reduced ARR compared to the previous year (0.3 ± 0.6 vs 1.2 ± 0.5; p < 0.001). After 12 and 24 months 63 and 37 % of patients had NEDA-3. Previous use of immunosuppressants and an ARR ≥1 in the 2 years predicted disease activity. Fingolimod significantly reduce disease activity in active RRMS patients, with no severe/unexpected safety issues. Patients previously treated with immunosuppressants and with a higher ARR at baseline may respond less to fingolimod treatment

Humanism in the Age of COVID-19: Renewing Focus on Communication and Compassion

The global COVID-19 pandemic has become one of the largest clinical and operational challenges faced by emergency medicine, and our EDs continue to see increased volumes of infected patients, many of whom are not only ill, but acutely aware and fearful of their circumstances and potential mortality. Given this, there may be no more important time to focus on staff-patient communication and expression of compassion.However, many of the techniques usually employed by emergency clinicians to provide comfort to patients and their families are made more challenging or impossible by the current circumstances. Geriatric ED patients, who are at increased risk of severe disease, are particularly vulnerable to the effects of isolation.Despite many challenges, emergency clinicians have at their disposal a myriad of tools that can still be used to express compassion and empathy to their patients. Placing emphasis on using these techniques to maximize humanism in the care of COVID-19 patients during this crisis has the potential to bring improvements to ED patient care well after this pandemic has passed

Muscular, skeletal and dental characteristics in children with posterior crossbite after and before of rapid maxillary expansion

Orientador: Maria Beatriz Duarte GaviãoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de PiracicabaResumo: O objetivo da presente pesquisa foi avaliar as características musculares, esqueléticas e dentárias em crianças antes e após o tratamento da mordida cruzada posterior (MCP) com expansão rápida da maxila. No capítulo 1, a espessura do músculo masseter e medidas esqueléticas e dentárias foram avaliadas em crianças, de ambos os gêneros (7-10 anos), divididas nos seguintes grupos: grupo com MCP bilateral (n=13), grupo com MCP unilateral (n=18) e grupo com oclusão normal (ON, n=32). Para avaliação da espessura muscular do masseter foi utilizado o equipamento de ultrasom, nas posições de repouso e máxima intercuspidação. Modelos de gesso e cefalogramas posteroanteriores foram obtidos e 5 medidas esqueléticas (largura maxilar, largura mandibular, razão maxilar/mandibular e os ângulo J-CO-AG), bem como 5 medidas dentárias (largura intermolar maxilar e mandibular, razão entre as larguras intermolares superior/inferior e a distancia rafe palatina-1ºs molares superiores de ambos os lados) foram analisadas. Os resultados demonstraram que os grupos com MCP bilateral e unilateral apresentaram atresia maxilar esquelética e dentária devido principalmente à constrição da base apical maxilar. Não houve diferenças significativas entre os grupos MCP bilateral e MCP unilateral, entretanto, somente o grupo MCP unilateral apresentou um maior ângulo J-CO-AG (no lado cruzado) em relação ao grupo com ON. As diferenças em relação à espessura muscular do masseter não foram significativas nem entre os lados e nem entre os grupos. Correlações significativas entre medidas esqueléticas e dentárias foram observadas apenas no grupo com ON. No capítulo 2, a atividade eletromiográfica (EMG) dos músculos mastigatórios e as medidas esqueléticas e dentárias foram avaliadas em crianças com MCP funcional (n=17), antes e após o tratamento com expansão rápida da maxila; este grupo foi comparado com crianças com ON (n=15). A atividade EMG do masseter e temporal anterior foi registrada com eletrodos de superfície durante a mastigação habitual por 20 s. Foram realizadas as mesmas medidas transversais esqueléticas e dentárias citadas no capítulo 1. Todos os exames foram realizados antes (T1) e após a expansão maxilar (T2). O intervalo médio entre os tempos foi de 10,6 meses. Os resultados demonstraram que a atividade EMG dos músculos mastigatórios aumentou significativamente após o tratamento, bem como a maioria das medidas transversais esqueléticas e dentárias, sendo os efeitos esqueléticos mais significativos do que os dentários. De acordo com os estudos, concluiu-se que crianças com MCP apresentam diferenças entre as variáveis esqueléticas e dentárias em relação ao grupo com ON. O tratamento da MCP através da expansão rápida da maxila corrigiu essas diferenças, bem como promoveu o aumento das atividades EMG dos músculos masseter e temporal anterior durante a mastigação habitual. Estes achados indicam que o tratamento precoce da MCP favorece a obtenção de condições morfológicas e funcionais adequadas para um melhor desenvolvimento do sistema estomatognático.Abstract: The aim of the present research was to evaluate the muscular, skeletal and dental characteristics in children before and after the treatment of posterior crossbite (PCB) by rapid maxillary expansion. In chapter 1, the masseter muscle thickness and the skeletal and dental measurements were evaluated in children, from both genders (7-10 years), divided in the following groups: group with bilateral PCB (n=13), group with unilateral PCB (n=18) and normal occlusion group (NO , n=32). The ultrasound equipment was used for the evaluation of masseter muscle thickness, in rest and maximal intercuspation positions. Dental casts and posteroanterior cephalograms were obtained and five skeletal (maxillary width, maxillary to mandibular width ratio, manibular width and J-CO-AG angles) and five dental measurements (maxillary intermolar width, maxillary to mandibular intermolar width ratio, mandibular intermolar width and distances from midpalatal raphe to upper first molar in both sides) were analyzed. The results showed that the groups with bilateral and unilateral PCB presented skeletal and dental atresia due to the constriction of maxillary apical base. There were no significant differences between the bilateral and unilateral PCB groups, however, only the unilateral PCB group presented a larger J-CO-AG angle (on crossbite side) in relation to the NO group. The differences related do masseter muscle thickness were not significant nor between sides nor between groups. Significant correlations between skeletal and dental measurements were observed only in the NO group. In chapter 2, the electromyographic (EMG) activity of masticatory muscles and the skeletal and dental measurements were evaluated in children with functional PCB (n=17) before and after the treatment with rapid maxillary expansion; this group was compared to children with NO (n=15). The EMG activity of masseter and anterior temporalis was recorded with superficial electrodes during habitualchewing for 20 s. The same transversal skeletal and dental measurements cited inchapter 1 were used. All exams were performed before (T1) and after (T2) maxillary expansion. The mean interval between times was 10.6 months. The results showed that the EMG activity of masticatory muscles significantly increased after treatment, as while as the majority of transversal skeletal and dental measurements,being the skeletal effects more significant than the dental ones. According to the studies, it was concluded that children with PCB present differences between skeletal and dental measurements in relation to the NO group. The PCB treatment with rapid maxillary expansion corrected these differences, and induced an increase in EMG activities of masseter and anterior temporalis muscles during habitual chewing. These findings indicate that early treatment of PCB create morphological and functional conditions proper to a better development of stomatognathic system.DoutoradoOdontopediatriaDoutor em Odontologi

Primary cutaneous Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL) in a patient taking fingolimod

A 55-year-old man with relapsing-remitting multiple sclerosis on fingolimod presented to the dermatology clinic with skin lesions on the left temple and cheek. Histopathology showed a diffuse infiltrate of enlarged, atypical lymphocytes throughout the dermis with an overlying grenz zone and a subpopulation of scattered smaller lymphocytes and plasma cells. Epstein-Barr virus-encoded RNA in situ hybridization stain was positive. Based on the morphologic and immunophenotypic findings, a diagnosis of EBV-positive diffuse large B-cell lymphoma was made. This case aims to raise awareness for the dermatologist that patients on fingolimod may be at increased risk of lymphoproliferative disorders

Baseline characteristics associated with NEDA-3 status in fingolimod-treated patients with relapsing-remitting multiple sclerosis

Abstract Background Fingolimod is an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) and there is class I evidence that it is superior to standard care in reducing relapse rate. However, real-world data investigating its effectiveness and potential predictors of response are still scarce. Objective To estimate (i) the proportion of fingolimod-treated patients who achieved the no evidence of disease activity (NEDA-3) status; and (ii) to determine which baseline (i.e. at treatment start) clinical and magnetic resonance imaging (MRI) variables were associated with better outcomes. Methods We collected clinical and MRI data of RRMS patients treated with fingolimod and followed-up for 24 months. The proportion of patients who had NEDA-3 - i.e. absence of relapses, sustained Expanded Disability Status Scale (EDSS) worsening and radiological activity on MRI - was estimated. A Cox proportional hazard model was carried out to investigate which baseline characteristics were associated with the NEDA status at follow-up. Results We collected data of 201 patients who started fingolimod. Of them, 24 (12%) were treatment-naïve, 115 (58%) were switched after failing a self-injectable drug, and 60 (30%) switching from natalizumab. Five patients who discontinued fingolimod early (within 3 months) (bradycardia, n = 2; leukopaenia, n = 2; macular oedema, n = 1) were removed from the analysis. At follow-up, 118 (60%) patients achieved the NEDA-3 status, while 78 experienced clinical and/or MRI activity. The risk of not achieving the NEDA-3 status was associated with higher baseline EDSS score (hazard ratio [HR] = 1.18, p = 0.024) and more relapses in the 12 months prior to fingolimod start (HR = 1.61, p = 0.014). Conclusion Our findings suggest that fingolimod may lead to a better control of the disease if started in patients with a less aggressive disease (i.e. fewer pre-treatment relapses and milder disability level), thus supporting its possible role as an early treatment for MS

A experiência da vida real com complicações cardiovasculares na primeira dose de fingolimode

Fingolimod is a new and efficient treatment for multiple sclerosis (MS). The drug administration requires special attention to the first dose, since cardiovascular adverse events can be observed during the initial six hours of fingolimod ingestion. The present study consisted of a review of cardiovascular data on 180 patients with MS receiving the first dose of fingolimod. The rate of bradycardia in these patients was higher than that observed in clinical trials with very strict inclusion criteria for patients. There were less than 10% of cases requiring special attention, but no fatal cases. All but one patient continued the treatment after this initial dose. This is the first report on real-life administration of fingolimod to Brazilian patients with MS, and one of the few studies with these characteristics in the world.Fingolimode é um tratamento novo e eficaz para esclerose múltipla (EM). A administração desta droga requer atenção especial para a primeira dose, uma vez que eventos adversos cardiovasculares podem ser observados nas seis horas iniciais da ingestão de fingolimode. O presente estudo consistiu de uma revisão de dados cardiovasculares de 180 pacientes com EM ao receberem a primeira dose de fingolimode. A taxa de bradicardia nestes pacientes foi maior do que aquele observada em estudos clínicos que tem critérios de inclusão muito rigorosos para seleção de pacientes. Menos de 10% dos casos necessitou de atenção especial, mas não houve casos fatais. Todos os pacientes exceto por um continuaram o tratamento após esta dose inicial. Este é o primeiro relato de dados de administração de fingolimode na vida real de pacientes brasileiros com EM, e um dos poucos trabalhos com estas características no mundo.Universidade Metropolitana de Santos Departamento de NeurologiaUniversidade Positivo Departamento de NeurologiaUniversidade Federal do Paraná Departamento de NeurologiaUniversidade Estadual de Campinas Departamento de NeurologiaUniversidade Federal de Juiz de Fora Departamento de NeurologiaHospital de Clínicas de Porto Alegre Departamento de NeurologiaPontifícia Universidade Católica Sorocaba Departamento de NeurologiaClínica Holus MedServiceHospital Beneficência Portuguesa de São Paulo Departamento de NeurologiaCentro Hospitalar Unimed Departamento de NeurologiaUniversidade Federal Fluminense Departamento de NeurologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de NeurologiaHospital de Base do Distrito Federal Departamento de NeurologiaInstituto de Neurologia de Curitiba Departamento de NeurologiaUNIFESP, Depto. de NeurologiaSciEL