Controversias en neuroinmunología: esclerosis múltiple, vacunación, SARS-CoV-2 y otros dilemas / Controversies in neuroimmunology: multiple sclerosis, vaccination, SARS-CoV-2 and other dilemas

La neuroinmunología es una disciplina que cada vez amplía más sus horizontes en la comprensión de las enfermedades neurológicas. Contemporáneamente, y a la luz de los nexos fisiopatológicos de las enfermedades neurológicas y la inmunología, se han planteado enfoques diagnósticos y terapéuticos específicos. A pesar de los importantes avances de esta disciplina, existen múltiples dilemas que le conciernen y se filtran en la práctica clínica. En esta revisión, se presentan y discuten 15 controversias, las cuales se construyen con la información clínica disponible más actualizada. Los temas incluidos son: disminución de esteroides en recaídas de esclerosis múltiple; recomendaciones terapéuticas en esclerosis múltiple a la luz de la pandemia por el SARS-CoV-2; evidencia de vacunación en esclerosis múltiple y en otras enfermedades desmielinizantes; panorama actual del síndrome clínico y radiológico aislado; y fallas terapéuticas en esclerosis múltiple; además, criterios para suspender las terapias modificadoras de la enfermedad; evidencia del manejo en recaídas leves; recomendaciones para la profilaxis contra Strongyloides stercolaris; utilidad de un segundo ciclo de inmunoglobulina en el síndrome de Guillain-Barré; criterios para diferenciar una polineuropatía crónica desmielinizante inflamatoria de inicio agudo de un síndrome de Guillain-Barré y, utilidad de la enzima convertidora de angiotensina en neurosarcoidosis. En cada una de las controversias, se presenta la problemática general y se ofrecen recomendaciones específicas que pueden adoptarse en la práctica clínica diaria.

Neuroimmunology is a discipline that increasingly broadens its horizons in the understanding of neurological diseases. At the same time, and in front of the pathophysiological links of neurological diseases and immunology, specific diagnostic and therapeutic approaches have been proposed. Despite the important advances in this discipline, there are multiple dilemmas that concern and filter into clinical practice. This article presents 15 controversies and a discussion about them, which are built with the most up-to-date evidence available. The topics included in this review are: steroid decline in relapses of multiple sclerosis; therapeutic recommendations in MS in light of the SARS-CoV-2 pandemic; evidence of vaccination in multiple sclerosis and other demyelinating diseases; overview current situation of isolated clinical and radiological syndrome; therapeutic failure in multiple sclerosis, as well as criteria for suspension of disease-modifying therapies; evidence of the management of mild relapses in multiple sclerosis; recommendations for prophylaxis against Strongyloides stercolaris; usefulness of a second course of immunoglobulin in the Guillain-Barré syndrome; criteria to differentiate an acute-onset inflammatory demyelinating chronic polyneuropathy versus Guillain-Barré syndrome; and, the utility of angiotensin-converting enzyme in neurosarcoidosis. In each of the controversies, the general problem is presented, and specific recommendations are offered that can be adopted in daily clinical practice.

Real-world effectiveness of natalizumab treatment in patients with relapsing multiple sclerosis in Argentina and Chile / Efectividad en el mundo real del tratamiento con Natalizumab para pacientes con esclerosis múltiple recurrente en Argentina y Chile

ABSTRACT Background: The real-world effectiveness of natalizumab in people with relapsing multiple sclerosis (PwRMS) in Argentina and Chile has not been reported. Objective: To evaluate the effectiveness of natalizumab treatment in PwRMS in Argentina and Chile, in clinical practice. Methods: We conducted a multicenter retrospective and observational study. We reviewed the medical records of PwRMS who had been treated with natalizumab for at least one year, without any interruption in MS treatment that lasted more than 12 weeks. We analyzed changes in annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score and magnetic resonance imaging (MRI). Results: We enrolled 117 PwRMS treated with natalizumab. Natalizumab treatment was associated with a significant reduction in ARR from baseline after one year and two years of treatment (from 1.97 to 0.06 and 0.09 respectively; p<0.01 at each time point). From baseline, EDSS scores were reduced by 0.71 and 0.73 points at one and two years, respectively (p<0.01). No worsening of disability was observed in 82.9 and 67.5% of PwRMS at one and two years, respectively. The improvement in disability was 44.4% at one year and 39.3% at two years. During natalizumab treatment, the number of relapse-related hospitalizations was significantly reduced (p<0.01). MRI lesions (new/enlarging T2 or gadolinium-enhancing) were significantly reduced, compared with baseline. No evidence of disease activity was observed in 65% at two years of natalizumab treatment. Conclusions: Natalizumab significantly reduced disease activity in PwRMS in Argentina and Chile, in clinical practice. Natalizumab also decreased the number of hospitalizations compared with pre-natalizumab treatment.

RESUMEN Antecedentes: La efectividad de Natalizumab en personas con esclerosis múltiple recurrente (PwRMS) en Argentina y Chile no se ha reportado. Objetivo: Evaluar la efectividad del tratamiento con Natalizumab en PwRMS en Argentina y Chile en la práctica clínica. Métodos: Estudio multicéntrico, retrospectivo y observacional. Revisamos los registros médicos de PwRMS que fueron tratados con Natalizumab al menos 1 año, sin interrupción de tratamiento para EM durante más de 12 semanas. Analizamos los cambios en la tasa anualizada de recaídas (ARR), escala de discapacidad expandida (EDSS) y resonancia magnética (MRI). Resultados: Se incluyeron 117 PwRMS. El tratamiento con Natalizumab se asoció con una reducción significativa de la tasa anualizada de recaídas (ARR) cada 1 y 2 años (de 1.97 a 0.06 y 0.09, respectivamente; p<0.01 en ambos casos). El EDSS se redujo 0,71 y 0,73 puntos al año 1 y 2, respectivamente (p<0,01). No se observó empeoramiento del EDSS en 82,9 y 67,5% de los PwRMS al año 1 y 2, respectivamente. La mejoría del EDSS fue 44,4 y 39,3% al año 1 y 2, respectivamente. El número de hospitalizaciones se redujo significativamente (p<0,01). Las lesiones en MRI (nuevas/agrandadas en T2 o con realce con gadolinio) se redujeron significativamente en comparación con el valor basal. No se observó evidencia de actividad de la enfermedad en el 65% de los PwRMS a 2 los años. Conclusiones: Natalizumab redujo significativamente la actividad de la enfermedad en PwRMS de Argentina y Chile en la práctica clínica. Además, disminuyó el número de hospitalizaciones comparado con el tratamiento previo.

Esclerosis múltiple: reacciones adversas a medicamentos en pacientes bajo ley 20850, Hospital Regional de Talca / Multiple sclerosis: adverse drug reactions in patients under law 20850, Hospital Regional de Talca

INTRODUCTION: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, which occurs in up to 85% of cases as relapsing remitting (RR), with episodes of neurological dysfunction partially forwarded. Its treatment in Chile is financially protected by the Explicit Health Guarantees (GES) and Law 20,850 on high-cost diseases. The Regional Hospital of Talca (HRT) has 25 patients benefiting from Law 20,850 in treatment with second-line biologic therapy. Adverse reactions (RAM) to the use of these drugs have been described and to date there are no case reports or studies of significant adverse events in Chile. Objectives: To present the experience of the use of biologic therapy in EMRR in HRT, in relation to adverse events. METHODS: A review of the current guidelines in Chile for the treatment of relapsing-remitting multiple sclerosis and the protocol of law 20,850 was carried out, the clinical records of 25 patients benefiting from the law in the HRT were reviewed, with emphasis on the adverse events presented before First and second line therapies and the con sequences of these events on the continuity of therapy. RESULTS: Half of the patients who started their treatment with first-line drugs had adverse effects, of which 28% involved a change in therapy, the remaining changed from therapy due to failure to treatment. Of the 26 patients included in the sample, 24 are currently using second-line drugs. The profile of adverse effects should be a variable to consider when indicating a therapy for MS.

Natalizumab in patients with multiple sclerosis in Colombia: a case series / Natalizumab en pacientes con esclerosis múltiple en Colombia: una serie de casos

SUMMARY INTRODUCTION: Natalizumab is a humanized monoclonal antibody prescribed in the treatment of multiple sclerosis, the most prevalent chronic and inflammatory disease of the central nervous system (CNS). NEDA (no evidence of disease activity) status is the goal of multiple sclerosis treatment. METHODOLOGY: The clinical records of 22 patients with multiple sclerosis, followed for a mean of 9.2 years (range: 1.9 -18.3 years) between 2000 and 2018 were analyzed. These patients received treatment with natalizumab in a high-complexity neurological outpatient clinic in Bogotá, Colombia. RESULTS: Eighteen patients (82%) reached NEDA status within a median time of six months. Seven patients (32%) tested positive for anti-JC virus antibodies. However, none of them developed progressive multifocal leukoencephalopathy. During the evaluation period, five patients (23%) presented new lesions and 17 patients (77%) had relapses before reaching NEDA status. CONCLUSIONS: This study gave an exploratory analysis of the characteristics of a series of patients with MS in the Colombian context. In the retrospective analysis, it was observed that more than 80% of the studied sample that received treatment with natalizumab, reached NEDA status. Despite the methodological limitations inherent to this type of study and sample size, it suggests that natalizumab could be an appropriate medication for the management of multiple sclerosis in Colombia.

RESUMEN INTRODUCCIÓN: Natalizumab es un anticuerpo monoclonal humanizado empleado en el tratamiento de esclerosis múltiple, la enfermedad crónica e inflamatoria más prevalente del sistema nervioso central. El estado de NEDA (sin evidencia de actividad de la enfermedad) es el objetivo del tratamiento de la esclerosis múltiple. METODOLOGÍA: Se analizaron las historias clínicas de 22 pacientes con esclerosis múltiple que fueron seguidos durante una media de 9,2 años (rango: 1,9-18,3 años) entre 2000 y 2018. Estos pacientes recibieron tratamiento con natalizumab en una clínica ambulatoria neurológica de alta complejidad en Bogotá, Colombia. RESULTADOS: Dieciocho pacientes (82)% alcanzaron el estado NEDA en un tiempo medio de seis meses. Siete pacientes (32%) dieron positivo para anticuerpos anti-virus JC. Sin embargo, ninguno desarrolló leucoencefalopatía multifocal progresiva. Durante el periodo de seguimiento cinco pacientes (23%) presentaron nuevas lesiones y 17 pacientes (77%) tuvieron recaídas antes de alcanzar el estado NEDA. CONCLUSIONES: Este estudio provee un análisis exploratorio de las características de una serie de pacientes colombianos con esclerosis múltiple.. En el análisis retrospectivo, se observó que más de 80% de ellos alcanzó el estado NEDA. A pesar de las limitaciones metodológicas inherentes al tipo de estudio y el tamaño de la muestra, este estudio sugiere que natalizumab podría ser un medicamento apropiado para el tratamiento de la esclerosis múltiple. en Colombia.

Impacto orçamentário de natalizumabe para o tratamento em primeira linha da esclerose múltipla remitente-recorrente altamente ativa sob a perspectiva do sistema de saúde privado brasileiro / Budget impact analysis of the adoption of natalizumab as first-line treatment of highly active relapsing-remitting multiple sclerosis from a Brazilian private payer perspective

Objetivos: Os objetivos deste estudo são calcular o custo de um surto de esclerose múltipla sob a perspectiva de uma operadora de saúde privada e o impacto orçamentário da adoção de natalizumabe em primeira linha para esclerose múltipla remitente-recorrente altamente ativa (EMRRAA). Métodos: Para o cálculo do custo do surto, duas abordagens foram adotadas: para surtos que não levam a hospitalizações, foi aplicada uma pesquisa a 33 médicos neurologistas para identificação do consumo de recursos. Microcusteio foi realizado com base em bases de dados públicas. Para o cálculo do custo de surtos que levam a hospitalizações, foi utilizada uma base de contas médicas. Para o cálculo do impacto orçamentário, foi construído um modelo baseado em prevalência. Foram assumidos os seguintes custos: custo de aquisição de natalizumabe, custo de infusão de natalizumabe e custo de surtos. Taxa de ocorrência de surtos para natalizumabe e para seus comparadores, disponível apenas no sistema público, foi obtida em estudos clínicos e metanálises. O caso-base foi realizado considerando-se uma operadora que atende 100 mil vidas na região Sudeste. Análise de sensibilidade foi realizada. Resultados: O custo calculado de um surto foi de R$ 14.157,21. O impacto orçamentário calculado para adoção de natalizumabe para EMRRAA foi de R$ 0,64 por beneficiário por ano, ou 0,02% das despesas assistenciais de uma operadora de saúde suplementar, ou 0,02% de suas receitas de contraprestações. A análise de sensibilidade confirma que o impacto não chega a 1 real por beneficiário por ano e atinge, no máximo, 0,03% das despesas assistenciais. Conclusão: Dados os altos benefícios clínicos de natalizumabe, o impacto orçamentário de sua adoção para primeira linha de EMRRAA é considerado baixo. O impacto pode estar superestimado, visto que não foram considerados custos de progressão da doença.

Objetivos: The goals of this study are to evaluate the cost of a multiple sclerosis relapse and the budget impact of adopting natalizumab as first-line therapy for HARRMS, both from a private payer perspective. Methods: For calculating the cost of a relapse, two approaches were adopted: for relapses not resulting in hospitalizations, a research with 33 physicians was made to obtain resource utilization data. Microcosting was performed using public data sources. For calculating costs of relapses leading to hospitalizations, we analyzed a claims database. To calculate the budget impact of adopting natalizumab as per its label indication, we built a prevalence-based model. The following costs were included: drug acquisition, drug infusion and relapses costs. The relapses rates for natalizumab and its comparators present in the public system were calculated based on clinical trials and meta-analysis. The base case was calculated assuming a hypothetical payer covering one hundred lives in the southeastern region of Brazil. Sensitivity analysis was performed. Results: The calculated relapse cost was R$ 14,157.21. The calculated budget impact for adopting natalizumab for HARRMS was R$ 0.64 per person per year, or 0.02% of the payer's healthcare expenditures, or 0.02% of its revenue. The sensibility analysis confirmed that the budget impact does not reach one real per person per year and does not exceed 0.03% of healthcare expenses. Conclusion: Given the high clinical benefits of adopting Tysabri, its budget impact can be considered low. The results might be overestimated, since disability progression costs were not accounted in the calculations

An experimental study to evaluate safety/toxicity of intravitreal natalizumab

Purpose: The purpose of this prospective experimental study was to evaluate the safety/toxicity of ?4?1 integrin blockade in rabbit retina using its monoclonal antibody (Natalizumab). Methods: Twelve New Zealand albino rabbits were divided into three groups (n = 4). Unilateral intravitreal injections of three different concentrations of natalizumab were performed in every rabbit of each group (Group A: 0.625 mg, Group B: 1.25 mg, and Group C: 2.5 mg). Baseline electroretinogram (ERG) and fundus photography were performed prior to injection. At days 1, 7, and 21 postinjection, ERG and fundus photography of each eye were performed. At last follow-up, Group C animals with highest drug concentration were sacrificed and the enucleated eyes were evaluated for retinal toxicity using transmission electron microscopy (TEM). Results: No difference in ERG responses was observed in eyes injected with low and intermediate concentration of natalizumab between day 0 and day 21. Furthermore, rabbits injected intravitreally with highest dose showed reduction in amplitude of “a” wave (P = 0.0017) and a reduction in amplitude of “b” wave of ERG at day 21 (P = 0.0117). TEM revealed changes in the outer plexiform layer and inner nuclear layer, suggestive of toxicity primarily to the photoreceptor synaptic terminals and bipolar cells. Conclusion: Low-dose (0.625 mg) and intermediate-dose (1.25 mg) intravitreal injection of natalizumab appears safe for rabbit retina. However, functional and anatomical changes were observed in rabbit retina following a high-dose (2.5 mg) intravitreal injection of a monoclonal antibody blocking ?4?1 integrin.

Serological profile of John Cunningham virus (JCV) in patients with multiple sclerosis / Perfil sorológico do vírus John Cunningham (JCV) em pacientes com esclerose múltipla

ABSTRACT Treatment options for multiple sclerosis (MS) have changed over the last few years, bringing about a new category of drugs with more efficient profiles. However, these drugs have come with a whole new profile of potential adverse events that neurologists have to learn well and quickly. One of the most feared complications of these MS treatments is progressive multifocal leukoencephalopathy caused by the reactivation of the John Cunningham virus (JCV). Objective: To identify the serologic profile of JCV in patients with MS. Methods: Data on serum antibodies for JCV were obtained using the enzyme-linked immunosorbent assay provided by the STRATIFY-JCV program. Results: A total of 1,501 blood tests were obtained from 1,102 patients with MS. There were 633 patients (57.1%) who were positive for antibodies for JCV and 469 patients who were negative (42.9%). Twenty-three patients became positive after initially having negative JCV antibody status. The rate of seroconversion was 18.5% over 22 months. Conclusion: The JCV serologic profile and seroconversion in Brazilian patients were similar to those described in other countries.

RESUMO As opções terapêuticas para esclerose múltipla (EM) modificaram-se ao longo dos últimos anos, trazendo uma nova categoria de drogas com melhor perfil de eficácia. No entanto, estas drogas vieram com um novo perfil de potenciais eventos adversos que exigem que o neurologista os reconheça bem e rapidamente. Uma das complicações mais temidas destes tratamentos para a EM é a leucoencefalopatia multifocal progressiva (LEMP), causada pela reativação do vírus John Cunningham (JCV). Objetivo: Identificar o perfil sorológico de JCV em pacientes com EM. Métodos: Dados sorológicos de JCV foram obtidos através do ensaio por enzimas imuno-adsorvidas (ELISA) fornecido pelo programa STRATIFY-JCV. Resultados: Um total de 1.501 testes sanguíneos foram obtidos de 1.102 pacientes com EM. O grupo teve 633 pacientes (57,1%) soropositivos para anticorpos anti-JCV e 469 pacientes negativos (42,9%). Vinte e três pacientes se tornaram posivitos após resultados iniciais negativos para anticorpos anti-JCV. A taxa de soroconversão foi 18,5% em 22 meses. Conclusão: O perfil sorológico do JCV e a soroconversão nos pacientes brasileiros foi semelhante àquela descrita em outros países.

Psoriasis durante el tratamiento con Natalizumab en paciente con esclerosis múltiple / Psoriasis during treatment with Natalizumab in multiple sclerosis patient

La prevalencia de psoriasis entre los pacientes con esclerosis múltiple oscila entre el 1,59 y el 7,7%. Estas entidades comparten características genéticas y patogénicas, donde el principal papel lo cumplen los linfocitos T (Th1-Th17), cuya reactivación desencadena la liberación de citoquinas proinflamatorias, favoreciendo el desarrollo de los eventos inflamatorios, característicos de ambas entidades. El natalizumab, usado en el tratamiento de pacientes con esclerosis múltiple puede desencadenar psoriasis, al bloquear alguna de las moléculas de adhesión o vías inflamatorias, que pueden ser compensadas por otras y producir reacciones inmunes paradójicas.

The prevalence of psoriasis among patients with multiple sclerosis ranges from 1.59 to 7.7%. They share genetic and pathogenic characteristics where the main role is fulfilled by T lymphocytes (Th1-Th17), its activation triggers the release of proinflammatory cytokines, favoring the development of inflammatory events characteristic of both entities. Natalizumab, used in the treatment of patients with multiple sclerosis can trigger psoriasis, blocking some of the adhesion molecules or inflammatory pathways, which can be compensate by other pathways, and produce paradoxical immune reactions.

Multiple sclerosis risk perception and acceptance for Brazilian patients / Percepção e aceitação de risco em pacientes brasileiros com esclerose múltipla

ABSTRACT The perception of multiple sclerosis (MS) severity and risk associated with therapies might influence shared decision making in different countries. We investigated the perception of MS severity and factors associated with risk acceptance in Brazil in 96 patients with relapsing-remitting MS using a standardized questionnaire and compared this with two European cohorts. Multiple sclerosis was perceived as a very severe disease and the risk of developing progressive multifocal leukoencephalopathy due to natalizumab was seen as moderate to high. Seventy-six percent considered a risk of 1:1,000, or higher, an impediment for natalizumab use. Older age was the only variable associated with higher risk acceptance and our patients showed a more conservative profile than German and Spanish patients. Our patients perceived MS severity and progressive multifocal leukoencephalopathy risk similarly to elsewhere, but their willingness to take risks was more conservative. This should be considered when discussing therapeutic options and it might have an impact on guideline adaptations.

RESUMO A percepção de gravidade da esclerose múltipla (EM) e riscos associado a terapias podem influenciar a escolha de tratamento em diferentes países. Investigamos a percepção da gravidade da EM e fatores associados à aceitação de risco em 96 pacientes com EM remitente-recorrentecom um questionário e comparamos com duas coortes europeias. A EM foi percebida como muito grave e o risco de desenvolver leucoencefalopatia multifocal progressiva devido ao natalizumabe, como moderado a alto, sendo que76% consideraram um risco de 1: 1.000 ou maior como impeditivo deseu uso. Idade mais avançada foi a única variável associada àaceitação de risco mais elevado e nossos pacientes revelaram um perfil mais conservador do que os pacientes alemães e espanhóis. Esses dados devem ser considerados ao discutir opções terapêuticas e pode ter impacto nas adaptações de diretrizes locais.

Systematic review of the published data on the worldwide prevalence of John Cunningham virus in patients with multiple sclerosis and neuromyelitis optica / 한국역학회지

OBJECTIVES: John Cunningham virus (JCV) is a polyoma virus that infects humans, mainly in childhood or adolescence, and presents no symptomatic manifestations. JCV can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals, including those undergoing treatment for multiple sclerosis (MS) and neuromyelitis optica (NMO). PML is a severe and potentially fatal disease of the brain. The prevalence of JCV antibodies in human serum has been reported to be between 50.0 and 90.0%. The aim of the present study was to review worldwide data on populations of patients with MS and NMO in order to establish the rates of JCV seropositivity in these individuals.METHODS: The present review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used the following search terms: “JCV” OR “JC virus” AND “multiple sclerosis” OR “MS” OR “NMO” OR “neuromyelitis optica” AND “prevalence.” These terms were searched for both in smaller and in larger clusters of words. The databases searched included PubMed, MEDLINE, SciELO, LILACS, Google Scholar, and Embase.RESULTS: After the initial selection, 18 papers were included in the review. These articles reported the prevalence of JCV antibodies in the serum of patients with MS or NMO living in 26 countries. The systematic review identified data on 29,319 patients with MS/NMO and found that 57.1% of them (16,730 individuals) were seropositive for the anti-JCV antibody (range, 40.0 to 69.0%).CONCLUSIONS: The median worldwide prevalence of JCV among adults with MS or NMO was found to be 57.1%.

Systematic review of the published data on the worldwide prevalence of John Cunningham virus in patients with multiple sclerosis and neuromyelitis optica / 한국역학회지

OBJECTIVES: John Cunningham virus (JCV) is a polyoma virus that infects humans, mainly in childhood or adolescence, and presents no symptomatic manifestations. JCV can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals, including those undergoing treatment for multiple sclerosis (MS) and neuromyelitis optica (NMO). PML is a severe and potentially fatal disease of the brain. The prevalence of JCV antibodies in human serum has been reported to be between 50.0 and 90.0%. The aim of the present study was to review worldwide data on populations of patients with MS and NMO in order to establish the rates of JCV seropositivity in these individuals. METHODS: The present review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used the following search terms: “JCV” OR “JC virus” AND “multiple sclerosis” OR “MS” OR “NMO” OR “neuromyelitis optica” AND “prevalence.” These terms were searched for both in smaller and in larger clusters of words. The databases searched included PubMed, MEDLINE, SciELO, LILACS, Google Scholar, and Embase. RESULTS: After the initial selection, 18 papers were included in the review. These articles reported the prevalence of JCV antibodies in the serum of patients with MS or NMO living in 26 countries. The systematic review identified data on 29,319 patients with MS/NMO and found that 57.1% of them (16,730 individuals) were seropositive for the anti-JCV antibody (range, 40.0 to 69.0%). CONCLUSIONS: The median worldwide prevalence of JCV among adults with MS or NMO was found to be 57.1%.

Experiencia local con natalizumab en pacientes con enfermedad de Crohn refractaria a anti-TNF: casos clínicos / Natalizumab for the treatment of Crohns disease: report of three cases

Anti-tumor necrosis factor-α (TNF) agents have dramatically changed the management of Crohn’s Disease (CD). However, a significant number of these patients do not respond at all or cease to respond to antibodies against TNF. In this clinical situation, the options include intensification of anti-TNF therapy by either increasing the dose or by shortening the administration interval, the use of a second anti-TNF or medications with a different mechanism of action. Among the later, Natalizumab, a humanized IgG4 monoclonal antibody against α4β1 and α4β7 integrins, is safe and effective in inducing and maintaining remission in active CD patient’s refractory to anti-TNF. In spite of this, Natalizumab use has been limited because of an increased risk of progressive multifocal leukoencephalophaty which results from reactivation of the John Cunningham (JC) virus. However, the presence of antibodies against JC virus in serum can be used to reduce the risk for this complication. We report three patients with Crohn’s disease refractory to treatment with infliximab, who responded successfully to the use of Natalizumab.

Patients' satisfaction with and views about treatment with disease-modifying drugs in multiple sclerosis / Satisfação e pontos de vista dos pacientes com esclerose múltipla em tratamento com drogas modificadoras da doença

ABSTRACT Objective The treatment of multiple sclerosis (MS) with disease-modifying-drugs (DMDs) is evolving and new drugs are reaching the market. Efficacy and safety aspects of the drugs are crucial, but the patients’ satisfaction with the treatment must be taken into consideration. Methods Individual interview with patients with MS regarding their satisfaction and points of view on the treatment with DMDs. Results One hundred and twenty eight patients attending specialized MS Units in five different cities were interviewed. Over 80% of patients were very satisfied with the drugs in use regarding convenience and perceived benefits. The only aspect scoring lesser values was tolerability. Conclusion Parameters for improving treatment in MS must include efficacy, safety, and patient satisfaction with the given DMD.

RESUMO Objetivo O tratamento da esclerose múltipla (EM) com drogas-modificadoras-da-doença (DMDs) está evoluindo e novas drogas estão sendo comercializadas. Eficácia e segurança são aspectos cruciais nas medicações, porém a satisfação do paciente com o tratamento deve ser levada em consideração. Métodos Entrevista individual com pacientes com EM investigando a satisfação e ponto de vista desta população em relação ao tratamento com DMDs. Resultados Cento e vinte e oito pacientes atendidos em unidades especializadas de EM de cinco cidades diferentes foram entrevistados. Mais de 80% dos pacientes estava bastante satisfeito com as medicações utilizadas, considerando aspectos de conveniência de uso e benefício das drogas. O único aspecto que pontuou menos foi tolerabilidade. Conclusão Parâmetros para melhor tratamento de EM devem incluir eficácia, segurança e satisfação dos pacientes com a DMD prescrita.

Safety of switching from natalizumab straight into fingolimod in a group of JCV-positive patients with multiple sclerosis / Segurança na mudança direta de natalizumabe para fingolimode em um grupo de pacientes com esclerose múltipla e positivos para JCV

ABSTRACT Objective 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 switching.

RESUMO Objetivo Avaliar 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 medicações.

Natalizumab-Related Progressive Multifocal Leukoencephalopathy-Immune Reconstitution Inflammatory Syndrome: A Case Report Highlighting Clinical and MRI Features

Multiple sclerosis (MS) patients treated with natalizumab often face the uncommon but severe complication of developing progressive multifocal leukoencephalopathy (PML). PML may be further complicated by immune reconstitution inflammatory syndrome (IRIS) after the removal of the drug. Since both PML and IRIS are associated with high morbidity and mortality rates, early clinical and radiological diagnosis of these complications is of paramount importance. Here, we report a case of an adult male patient who was diagnosed with PML after receiving natalizumab therapy for 6 years for the treatment of MS. Upon cessation of natalizumab, he presented with a paradoxical worsening of clinical and radiological findings consistent with an inflammatory brain injury due to IRIS. He was treated with high dose corticosteroid therapy followed by a gradual improvement in clinical and imaging findings. This article illustrates the magnetic resonance imaging (MRI) features of natalizumab‑associated PML-IRIS, along with a brief overview of its clinical features, complications and management strategies.

Natalizumab treatment in multiple sclerosis: the experience from two Brazilian MS centers / Natalizumabe no tratamento da esclerose múltipla: a experiência de dois centros brasileiros

Objective Analyze the demographics, clinical characteristics, efficacy and safety of natalizumab treatment in Brazilian patients with multiple sclerosis (MS) followed up for at least 12 months, in two tertiary MS care centers in São Paulo.Method We evaluated the effect of natalizumab treatment on annualized relapse rate and disability progression in 75 patients with MS treated with natalizumab for at least 12 months. A subgroup analysis was performed to evaluate efficacy of natalizumab treatment in patients with Expanded Disability Status Scale (EDSS) ≤ 3.0 vs patients with EDSS > 3.Results Patients treated for at least one year with natalizumab showed a 91% reduction in aRR, as well and an improvement in neurological disability. The impact of natalizumab treatment was greater in patients with EDSS < 3.0. Overall, natalizumab was safe but one patient developed progressive multifocal leukoencephalopathy.Conclusion Natalizumab as a third line therapy is safe and efficacious, especially in patients with mild neurological disability.

Objetivo Analisar as características clínicas e demográficas, assim como a eficácia e segurança do tratamento com natalizumabe (usado em terceira linha), por no mínimo 12 meses, em pacientes brasileiros acompanhados em dois centros de tratamento de esclerose múltipla, na cidade de São Paulo.Método Avaliamos o efeito do tratamento com natalizumabe na taxa anualizada de surto (aRR) e progressão de incapacidade (medida por Expanded Disability Status Scale (EDSS)) em 75 pacientes tratados por, no mínimo 12 meses. Realizamos uma análise de subgrupo em pacientes com EDSS ≤ 3,0 e com EDSS > 3, para avaliar o impacto no tratamento, considerando-se o grau de incapacidade neurológica.Resultados O tratamento com natalizumabe, por pelo menos um ano, reduziu a aRR em 91%, assim como melhorou a incapacidade neurológica. Em pacientes com EDSS ≤ 3,0 observamos um impacto maior do tratamento na incapacidade neurológica, reduzindo sua progressão em 51%, durante o período do estudo. O tratamento com natalizumabe é seguro, porém um paciente desenvolveu leucoencefalopatia multifocal progressiva.Conclusão O tratamento com natalizumabe, em terceira linha terapêutica é seguro e eficaz especialmente, em pacientes com incapacidade neurológica leve (EDSS ≤ 3.0).

Natalizumab treatment for multiple sclerosis: updates and considerations for safer treatment in JCV positive patients / Tratamento com Natalizumabe para esclerose múltipla: atualizações e considerações para um tratamento mais seguro em pacientes positivos para o VJC

Natalizumab is currently one of the best options for treatment of patients with Multiple Sclerosis who have failed traditional prior therapies. However, prolonged use, prior immunosuppressive therapy and anti-JCV antibody status have been associated with increased risk of developing progressive multifocal leukoencephalopathy (PML). The evaluation of these conditions has been used to estimate risks of PML in these patients, and distinct (sometimes extreme) approaches are used to avoid the PML onset. At this time, the biggest issue facing the use of Natalizumab is how to get a balance between the risks and the benefits of the treatment. Hence, strategies for monitor JCV-positive patients undergoing Natalizumab treatment are deeply necessary. To illustrate it, we monitored JCV/DNA in blood and urine of a patient receiving Natalizumab for 12 months. We also bring to discussion the effectiveness of the current methods used for risk evaluation, and the real implications of viral reactivation.

Natalizumabe é atualmente uma das melhores opções para o tratamento de pacientes com Esclerose Múltipla que não respondem aos tratamentos tradicionais. No entanto, o seu uso prolongado, o uso de terapia imunossupressora prévia e o status sorológico antivírus JC têm sido associados com o risco aumentado de desenvolvimento de Leucoencefalopatia Multifocal Progressiva (LEMP). A avaliação destas condições tem sido utilizada para estimar os riscos do desenvolvimento de LEMP nestes pacientes, e abordagens distintas (por vezes extremas) são empregadas para evitar o aparecimento dessa patologia. Atualmente, o grande desafio está em obter um equilíbrio entre os riscos e os benefícios do tratamento com Natalizumabe. Assim, é crucial desenvolver estratégias para monitorar pacientes portadores do vírus JC sob tratamento com Natalizumabe. A título de ilustração, pesquisamos o vírus no sangue e na urina de um paciente sob tratamento durante 12 meses. Também discutimos a eficácia dos métodos atualmente utilizados para avaliação de riscos e as implicações reais de reativação viral.

Leucoencefalopatía multifocal progresiva asociada al uso de Natalizumab en un paciente con esclerosis múltiple. Primer caso en Latinoamérica. Hospital de San José - Bogotá 2013 / Progressive Multifocal Leukoencephalopathy associated with the use of Natalizumab in Patient with Multiple Sclerosis. First Case Report in Latin America Hospital de San Jose - Bogota, 2013

La Leucoencefalopatía Multifocal Progresiva (LMP) es una condición grave secundaria a la infección por virusJohn Cunningham (VJC) derivada de la deficiencia de inmunidad celular innata o adquirida. Se presenta el primercaso reportado en Latinoamérica de (LMP) asociada a Natalizumab (NZB) en un paciente con diagnóstico deesclerosis múltiple recaída-remisión, quien ingresa a urgencias con cuadro clínico de deterioro cognoscitivo,comportamental, motor y de lenguaje de curso progresivo. Se realizaron neuroimágenes con resonancia magnéticacerebral sugestivas de LMP, estudios de reacción en cadena de polimerasa en líquido cefalorraquídeopara virus JC, que resultaron negativos en dos oportunidades; el diagnóstico se confirmó mediante la técnica dehibridación in situ en biopsia cerebral. Se realiza este reporte con el fin de resaltar la importancia de la vigilanciaclínica y paraclínica en los pacientes con esclerosis múltiple que reciben NZB...

Progressive Multifocal Leukoencephalopathy (PML) is a serious condition secondary to John Cunninghamvirus (JCV) infection derived from an innate or acquired cellular immunity deficiency. We present the firstreported case in Latin America of PML associated with Natalizumab (NZB) in a patient with a diagnostic ofrelapsing – remitting multiple sclerosis, who entered the emergency room with progressive cognitive, behavioral,motor and language impairment. Neuroimaging performed with magnetic resonance imaging was suggestiveof PML. Polymerase chain reactions in cerebrospinal fluid for JC virus were conducted twice with negativeresults. Finally the diagnosis was confirmed by in situ hybridization technique on brain biopsy. This reportis made in order to highlight the importance of clinical and paraclinical monitoring in patients with multiplesclerosis receiving NZB...

Nearly one-half of Brazilian patients with multiple sclerosis using natalizumab are DNA-JC virus positive / Cerca de metade dos pacientes brasileiros recebendo natalizumabe para tratamento de esclerose multipla tem DNA-JC virus positivo

Objective Natalizumab is a new and efficient treatment for multiple sclerosis (MS). The risk of developing progressive multifocal leukoencephalopathy (PML) during the use of this drug has created the need for better comprehension of JC virus (JCV) infection. The objective of the present study was to assess the prevalence of JCV-DNA in Brazilian patients using natalizumab. Method Qualitative detection of the JCV in the serum was performed with real-time polymerase chain reaction (PCR). Results In a group of 168 patients with MS who were undergoing treatment with natalizumab, JCV-DNA was detectable in 86 (51.2%) patients. Discussion Data on JCV-DNA in Brazil add to the worldwide assessment of the prevalence of the JCV in MS patients requiring treatment with natalizumab. .

Objetivo Natalizumabe é um tratamento novo e eficaz para esclerose múltipla (EM). O risco constatado de desenvolver leucoencefalopatia multifocal progressiva (LEMP) durante o uso desta droga criou a necessidade de melhor estudar a infecção pelo vírus JC (JCV). O objetivo do presente estudo foi avaliar a prevalência de DNA-JCV em paciente brasileiros usando natalizumabe. Método Detecção qualitativa de JCV no soro foi realizada através de reação em cadeia por polimerase (PCR) em tempo real. Resultados DNA-JCV foi detectado em 86 pacientes (51,2%) de um grupo de 168 pessoas com EM recebendo tratamento com natalizumabe,). Discussão Dados do DNA-JCV no Brasil complementam as avaliações mundiais sobre a prevalência de JCV em pacientes com EM que necessitam tratamento natalizumabe. .

Progressive multifocal leukoencephalopathy: new concepts / Leucoencefalopatia multifocal progressiva: novos conceitos

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by reactivation of JC virus (JCV) in a setting of cellular immunosuppression. Originally, PML was observed in patients with advanced HIV infection, lymphoproliferative disorders and transplant recipients. However, the widespread use of HIV antiretroviral drugs and the new selective immunomodulatory and immunosuppressive medications, such as Rituximab and Natalizumab, has recently modified the epidemiology, clinical presentation and prognosis of PML. Herein, we discuss the new concepts on PML, emphasizing the recent modification in the epidemiology; the impact of new immunomodulatory treatments in the disease, PML-IRIS (Immune reconstitution inflammatory síndrome), new treatment strategies and other JCV related CNS diseases.

A leucoencefalopatia multifocal progressiva (LMP) é uma doença desmielinizante do sistema nervoso central (SNC) causada pela reativação do vírus JC (JCV) em um ambiente de imunossupressão celular. Originalmente, LMP foi descrita em pacientes com infecção avançada pelo HIV, doenças linfoproliferativas e transplantados. No entanto, a utilização generalizada de anti-retrovirais para a infecção pelo HIV e novos imunomoduladores seletivos e imunossupressores, como Rituximab e Natalizumab, modificaram recentemente a epidemiologia, apresentação clínica e prognóstico da LMP. Neste artigo, vamos discutir os novos conceitos sobre LMP, enfatizando a recente modificação na epidemiologia, o impacto de novos tratamentos imunomoduladores na doença, síndrome inflamatória da reconstituição imune, novas estratégias de tratamento e outras doenças relacionadas ao JCV no SNC.