Rebound activity after fingolimod cessation: A case - control study.

BACKGROUND: There has been an increase in the number of reports of multiple sclerosis (MS) rebound activity (RA), which is usually defined as a severe disease reactivation after natalizumab or fingolimod withdrawal that exceeds pre-treatment baseline inflammatory activity. The frequency and risk factors that could predict RA remain unknown. Fingolimod is currently the most frequently prescribed disease modifying therapy for MS in Argentina, so that there is a need to determine possible predictors of RA. OBJECTIVES: To identify risk factors for developing RA after fingolimod cessation; to describe RA characteristics, management and evolution. METHODS: The study was a multicenter, retrospective, case-control study of patients with MS who had discontinued fingolimod and were followed up to nine months after discontinuation. Demographic, clinical and paraclinical data was extracted, including age, gender, MS phenotype, reason for discontinuation, number of relapses during the year prior to suspension, time treated with fingolimod, EDSS before, during and after rebound, MRI findings. RESULTS: 26 cases of RA were matched 1:1 with patients without RA. The median time elapsed to RA was 50 days. 68% showed worsening of the EDSS in the evaluation at 3 months of RA. When compared with the control group, no difference was found in terms of age, gender, phenotype, EDSS at the moment of suspension, reason for discontinuation, number of relapses in the previous year, and time on therapy. CONCLUSION: In this case-controlled study, no risk factors could be identified to predict RA after fingolimod cessation. Further controlled, prospective, better powered studies are needed to confirm these findings.

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis.

With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS). The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS. The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties. As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments. This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.

Real-world effectiveness of natalizumab treatment in patients with relapsing multiple sclerosis in Argentina and Chile.

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.

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.

Radiologically isolated syndrome: from biological bases to practical management.

BACKGROUND: Technological advances and greater availability of magnetic resonance imaging have prompted an increment on incidental and unexpected findings within the central nervous system. The concept of radiologically isolated syndrome characterizes a group of subjects with images suggestive of demyelinating disease in the absence of a clinical episode compatible with multiple sclerosis. Since the description of this entity, many questions have arisen; some have received responses but others remain unanswered. A panel of experts met with the objective of performing a critical review of the currently available evidence. Definition, prevalence, biological bases, published evidence, and implications on patient management were reviewed. Thirty to 50% of subjects with radiologically isolated syndrome will progress to multiple sclerosis in 5 years. Male sex, age < 37 years old, and spinal lesions increase the risk. These subjects should be evaluated by a multiple sclerosis specialist, carefully excluding alternative diagnosis. An initial evaluation should include a brain and complete spine magnetic resonance, visual evoked potentials, and identification of oligoclonal bands in cerebrospinal fluid. Disease-modifying therapies could be considered when oligoclonal bands or radiological progression is present. CONCLUSION: At present time, radiologically isolated syndrome cannot be considered a part of the multiple sclerosis spectrum. However, a proportion of patients may evolve to multiple sclerosis, meaning it represents much more than just a radiological finding.