Generation of RRMS and PPMS specific iPSCs as a platform for modeling Multiple Sclerosis.

The advent of cellular reprogramming technology converting somatic cells into induced pluripotent stem cells (iPSCs) has revolutionized our understandings of neurodegenerative diseases that are otherwise hard to access and model. Multiple Sclerosis (MS) is a chronic demyelinating, inflammatory disease of central nervous system eventually causing neuronal death and accompanied disabilities. Here, we report the generation of several relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) iPSC lines from MS patients along with their age matched healthy controls from peripheral blood mononuclear cells (PBMC). These patient specific iPSC lines displayed characteristic embryonic stem cell (ESC) morphology and exhibited pluripotency marker expression. Moreover, these MS iPSC lines were successfully differentiated into neural progenitor cells (NPC) after subjecting to neural induction. Furthermore, we identified the elevated expression of cellular senescence hallmarks in RRMS and PPMS neural progenitors unveiling a novel drug target avenue of MS pathophysiology. Thus, our study altogether offers both RRMS and PPMS iPSC cellular models as a good tool for better understanding of MS pathologies and drug testing.

Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS.

OBJECTIVE: To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS). METHODS: In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test. RESULTS: Ocrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL. CONCLUSIONS: In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.

Prevention of rebound effect after natalizumab withdrawal in multiple sclerosis. Study of two high-dose methylprednisolone schedules.

BACKGROUND: Natalizumab (NTZ) is a disease-modifying treatment (DMT) in multiple sclerosis (MS) whose discontinuation can produce a "rebound effect", consisting of severe clinical deterioration and/or evidence of disease reactivation on magnetic resonance imaging (MRI). OBJECTIVE: To analyze the efficacy of two treatment schedules with intravenous methylprednisolone (IVMP) administered during the washout period of natalizumab (i.e., before starting another DMT) in preventing the rebound phenomenon. METHODS: Five-year retrospective study of NTZ withdrawals after at least 24 uninterrupted doses. Two IVMP schedules were tested. In schedule 1 (3-month washout), 1, 2, and 3 g of IVMP were administered on the first, second, and third month respectively. In schedule 2 (2-month washout), 1 and 2 g of IVMP were administered on the first and second month respectively. A new DMT was started 10 days after the end of each schedule. Rebound was defined as at least one clinical relapse plus rebound activity on MRI (>5 gadolinium-enhanced lesions and a number of new/T2-enhanced and/or gadolinium-enhanced lesions greater than before initiation of NTZ) during washout or at 6 months after new DMT initiation (6M-DMT). Clinical and MRI evaluations were performed at 3, 6, 12, and 24 months after initiation of the new DMT. RESULTS: Fifty patients (68% women) were included, with a mean (SD) age of 37.76 (10.88) years and pre-NTZ annualized relapse rate (ARR) of 1.78 (1.04). During NTZ therapy, mean Expanded Disability Status Scale (EDSS) score was 3.7 (1.73) and ARR was 0.23 (0.39). The ARR (mean of both schedules) was 0.1 (0.71) during washout and 0.32 (0.84) at 6M-DMT. Rebound was observed in 10% of cases (n = 5), with no significant clinical or radiological differences (p>0.05) between the two IVMP schedules. Rebound was observed in younger patients and was associated with new MRI lesions and higher ARR at 3M-DMT and 6M-DMT respectively, with no difference in EDSS after 2 years of follow-up. Neither the ARR before NTZ initiation nor the choice of new DMT after NTZ discontinuation was associated with development of rebound effect. CONCLUSIONS: Both IVMP schedules were well tolerated during NTZ washout and rebound was observed in only 10% of cases. In our experience, administration of IVMP during NTZ washout could reduce the possibility of a rebound effect.

Possible Influence of the Route of Treatment Administration on Treatment Adherence in Patients With Multiple Sclerosis.

PURPOSE: Multiple sclerosis is a chronic, demyelinating, and degenerative disease of the central nervous system with an immune-based pathologic origin. The present pilot study aimed to assess whether the change in the route of treatment administration is associated with a variation in adherence and whether there is a change in quality of life, treatment satisfaction, and fatigue. METHODS: Patients with relapsing-remitting multiple sclerosis who were >18 years of age and who used to receive immunomodulatory parenteral treatment and were ready to change administration route were eligible for the study. Data were collected at baseline and 3 months later. Adherence, quality of life, treatment satisfaction, and fatigue were measured via the following questionnaires: Morisky-Green questionnaire on patient-reported medication adherence, Multiple Sclerosis Quality of Life Instrument, Treatment Satisfaction Questionnaire for Medication, and Modified Fatigue Impact Scale. FINDINGS: The study sample included 30 patients (mean age, 43.2 years; age range, 24-71 years; 60% female and 40% male). There was a significant improvement in adherence (p = 0.048). Mean (SD) physical and mental health quality-of-life summary scores varied from 52.50 (24.15) and 54.13 (21.24) to 67.55 (20.92) and 62.30 (21.75) (p < 0.001 and p = 0.001, d = -0.426 and d = -0.643, respectively). In the Treatment Satisfaction Questionnaire for Medication, an improvement of the score was observed in effectiveness of the medication (p = 0.0041, d = -0.563), adverse effects of the medication (p < 0.001, d = -0.976), convenience of the medication (p < 0.001, d = -1.235), and global satisfaction (p = 0.006, d = -0.725). Patients had a higher mean (SD) score (45.13 [26.7]) on the Modified Fatigue Impact Scale while receiving injectable treatment compared with that obtained with oral treatment (34.86 [23.16]; p = 0.009, d = 0.41). IMPLICATIONS: When the route of administration changed from injectable to oral, there was an increase in adherence, quality of life, and degree of patient satisfaction with their treatment and a decrease in the degree of fatigue.

Capillary leak syndrome in neuromyelitis optica treated with rituximab.

61-year-old woman with Neuromyelitis optica (NMO) diagnosis treated with rituximab was referred to our hospital with severe hypovolemic shock and anasarca. The laboratory findings showed marked hemoconcentration and a decrease in total serum protein. She developed a multiple organ failure and died three hours later. We diagnosed the patient as having capillary leak syndrome (CLS). CLS is a very rare condition caused by unexplained episodic capillary hyperpermeability, which can be idiopathic or secondary to some conditions like infection, malignant disease and some drugs like monoclonal antibodies. We reported the first CLS case in NMO patient treated with rituximab.

Clinical and radiological control of highly active relapsing-remitting multiple sclerosis with first-line natalizumab.

A 33-year-old man with gait instability, weakness of the left lower extremity, decreased visual acuity in the left eye, and urgency and urine incontinence was diagnosed of relapsing-remitting multiple sclerosis. He was treated with natalizumab (300 mg intravenously every 4 weeks) as first-line therapy, which reached at 6 months a favorable clinical evolution and dramatic radiological improvement (T2-weighted lesion load decreased by 50% and no gadolinium-enhancing T1 lesions) sustained over the course of 8 years. This clinical case shows the efficacy of natalizumab in a real-world setting and, particularly, the sustained effect of this drug in the long term as demonstrated by persistent radiological improvement. Natalizumab can be considered as the treatment of choice in relapsing-remitting multiple sclerosis forms presenting with two relapses and gadolinium-enhancing (Gd+) lesions.

Prevalencia de la esclerosis múltiple en la Región de Murcia / Prevalence of multiple sclerosis in the Region of Murcia

Introducción. La esclerosis múltiple (EM) es una enfermedad inflamatoria desmielinizante del sistema nervioso central con patogenia inmunomediada. Recientes estudios indican un aumento de su prevalencia, y numerosos trabajos relacionan el virus de Epstein-Barr (VEB) con su etiología. Objetivo. Análisis de prevalencia de la EM en la Región de Murcia, incluyendo la descripción de las características clínicas en el momento del inicio de la enfermedad, y del estado serológico del VEB de los pacientes con EM. Pacientes y métodos. Estudio epidemiológico retrospectivo, tomando como muestra la población residente en el área sanitaria centro-oeste de la Región de Murcia (257.865 habitantes). Se analizan datos clínicos y serológicos extraídos de diferentes fuentes. Resultados. Prevalencia de la EM en la población estudiada: 88 casos/100.000 habitantes. Prevalencia de la EM junto con el síndrome desmielinizante aislado: 98,4 casos/100.000 habitantes. Incidencia media de la EM: 5,8 casos/100.000 habitantes/año. En el inicio de la EM, el 67,8% eran mujeres, el 81,9% presentaba un curso recurrente-remitente, la edad media era de 31,4 años, el sistema funcional más frecuentemente afectado era el sensitivo (45,1%), el inicio fue monofocal en el 55,4% y el grado de discapacidad en la Expanded Disability Status Scale era de 2,1 puntos. La seroprevalencia del VEB fue del 99,3%. La reactivación de la infección por VEB se relacionó con actividad clínica de EM en 10 pacientes (45,4%). Conclusiones. Actualmente, la prevalencia de la EM en la Región de Murcia es similar a la estimada en otras comunidades autónomas españolas. El estudio confirma la tendencia de incremento de prevalencia observada en las últimas décadas (AU)

Introduction. Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system with immunemediated pathogenesis. Recent research points to an increase in its prevalence, and a number of studies relate EpsteinBarr virus (EBV) with its aetiology. Aims. This study seeks to analyse the prevalence of MS in the Region of Murcia, and includes a description of the clinical characteristics at the time of onset of the disease, and of the EBV serological status of patients with MS. Patients and methods. We conducted a retrospective epidemiological study based on a sample consisting of the population living within the central-west healthcare area of the Region of Murcia (257,865 inhabitants). Clinical and serological data extracted from different sources were analysed. Results. Prevalence of MS in the population under study: 88 cases/100,000 inhabitants. Prevalence of MS together with isolated demyelinating syndrome: 98.4 cases/100,000 inhabitants. Mean incidence of MS: 5.8 cases/100,000 inhabitants/ year. At the onset of MS, 67.8% were females, 81.9% presented a relapsing-remitting course, the mean age was 31.4 years, the sensory system was the most frequently compromised (45.1%), onset was monofocal in 55.4% and the degree of disability on the Expanded Disability Status Scale was 2.1 points. The seroprevalence of EBV was 99.3%. The reactivation of EBV infection was related to the clinical activity of MS in 10 patients (45.4%). Conclusions. Currently, the prevalence of MS in the Region of Murcia is similar to that estimated in other Spanish autonomous regions. The study confirms the trend of increased prevalence observed over the last few decades (AU)

Spasticity in multiple sclerosis and role of glatiramer acetate treatment.

INTRODUCTION: Spasticity is one of the most disabling and difficult-to-treat symptoms shown by patients with multiple sclerosis, who often show a suboptimal and unsatisfactory response to classic treatment and new available nonpharmacological alternatives. Due to the progressive nature of this condition, the early management should be essential to improve long-term outcomes. METHODS: We performed a narrative literature review of the contribution of spasticity to the burden of multiple sclerosis and the potential role of classic disease-modifying drugs. RESULTS: Added to the underlying pathophysiology of spasticity, certain external factors and drugs such as interferon may exacerbate the existing condition, hence their awareness is crucial as part of an effective management of spasticity. Furthermore, the evidence for the effectiveness of glatiramer acetate in preventing spasticity in naïve patients and in those switching from interferon should not be ignored. CONCLUSIONS: This literature review proposes the examination of spasticity and the influence of classic disease-modifying agents on the level of existing condition among the variables to be considered when deciding on therapy for multiple sclerosis in clinical practice.

Tratamientos orales en esclerosis múltiple / Oral treatments in multiple sclerosis

La aparición de nuevas opciones terapéuticas modificadoras del curso de la enfermedad (MCE) en esclerosis múltiple recurrente-remitente (EMRR), con el denominador común de la vía oral de administración, mejora considerablemente las expectativas de los pacientes en términos de efectividad, tolerancia y adherencia al tratamiento frente a los fármacos disponibles en la actualidad. Que estos fármacos compartan la vía de administración no implica que sean equivalentes entre sí, ya que bajo el epígrafe "vía oral" se engloban fármacos con diferentes indicaciones, distintos mecanismos de acción y resultados heterogéneos en cuanto a eficacia y seguridad, que permiten personalizar el tratamiento en función de las características individuales de cada paciente. En la actualidad hay 4 tratamientos MCE orales disponibles o en avanzado estado de desarrollo clínico: fingolimod, teriflunomida, dimetilfumarato y laquinimod. En los ensayos pivotales frente a placebo, estas moléculas redujeron la tasa anualizada de brotes frente a placebo en un 54, 31, 53 y 23%, respectivamente, el riesgo de progresión de la discapacidad en un 31, 30, 38 y 36%, y el número de lesiones activas captantes de contraste en resonancia magnética en un 82, 80, 90 y 37%, respectivamente. El balance riesgo/beneficio sienta la indicación de fingolimod en casos de respuesta subóptima al tratamiento MCE inicialmente instaurado o en formas de EMRR grave de rápida evolución, mientras que el resto de moléculas pueden utilizarse como primera opción de tratamiento. La experiencia clínica con estos tratamientos aportará nuevos datos de efectividad y seguridad, que serán determinantes a la hora de establecer nuevos algoritmos terapéuticos (AU)

The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient’ s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms (AU)

[Oral treatments in multiple sclerosis]. / Tratamientos orales en esclerosis múltiple.

The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient' s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms.