Multiple sclerosis and aging: comorbidity and treatment challenges.

BACKGROUND: The prevalence of elderly patients with MS is increasing, in conjunction with the ageing general population. This review will examine the principal characteristics of elderly patients with MS and how the concomitant pathologies affect them. Finally, it will assess the impact of the medications on these patients and whether it would be safe to discontinue the disease-modifying treatment. METHODS: Searches using PubMed were conducted in October 2020 to collect studies assessing the impact of age and comorbidities on patients with MS. RESULTS: Several studies showed that aged patients develop concomitant pathologies that could worsen the disease's prognosis. Also, MS itself may be closely related to cognitive impairment, even though the exact etiopathogenic mechanism of it is still unclear. To date, safety and efficacy of currently available drugs remain unassessed in elderly populations. These treatments may not be beneficial in preventing the progression of disability in ageing people with no signs of inflammatory activity, and discontinuation of treatment is often discussed in this subgroup of patients. CONCLUSIONS: The presence of cardiovascular pathology, psychiatric disorders, diabetes or cancer is further associated with increased mortality in MS patients. The diagnosis and treatment of the disease is challenged by both age-related comorbidities and clinical variations compared to younger patients. It may be safe to discontinue treatment in elderly patients with no clinico-radiological activity.

Effectiveness of Fingolimod versus Natalizumab as Second-Line Therapy for Relapsing-Remitting Multiple Sclerosis in Spain: Second-Line GATE Study.

BACKGROUND: There is a lack of head-to-head studies comparing the efficacy of fingolimod (FIN) and natalizumab (NTZ) as second-line therapy for relapsing-remitting multiple sclerosis (RRMS). METHODS: Multicenter, observational study, in which, information of 388 patients randomly selected and treated with FIN or NTZ in routine clinical practice was retrospectively collected with the main objective of comparing the annualized relapse rate (ARR) over the first year, after FIN or NTZ treatment initiation. RESULTS: Mean ARR during the first year of treatment was 0.28 in FIN group and 0.12 in NTZ group (p = 0.0064); nevertheless, the difference between groups lost statistical significance when the propensity score analysis was performed. Time to disability -progression was similar in both treatment groups (12.3 ± 6.7 months in FIN, and 12.8 ± 0.1 months in NTZ; p = 0.4654). Treatment persistence after the first year of treatment was higher in patients treated with FIN (95%) than in those treated with NTZ (84%; p = 0.0014). CONCLUSIONS: After 12 months of treatment, both FIN and NTZ reduced the ARR, but ARR percent reduction was significantly higher with NTZ. Treatment persistence was higher in patients receiving FIN.

Treatment satisfaction with injectable disease-modifying therapies in patients with relapsing-remitting multiple sclerosis (the STICK study).

BACKGROUND: Treatment satisfaction in patients with relapsing-remitting multiple sclerosis (RRMS) may impact adherence and thus clinical outcomes. The objective of this study was to measure the satisfaction of patients with RRMS with injectable disease-modifying therapies (DMTs) and to evaluate the factors associated with treatment satisfaction. MATERIAL AND METHODS: In this observational retrospective study conducted in the neurology departments of 35 hospitals throughout Spain, demographic data, disease characteristics, and information on treatment with injectable DMTs were collected at a single scheduled visit. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM), version 1.4. Patients also answered complementary questions about the factors that might affect treatment satisfaction. The data collected were analyzed descriptively. A regression model was used to explore the factors associated with treatment satisfaction. RESULTS: The study included 445 patients (mean±SD age, 41±10.2 years; two-thirds women). The percentages treated with each DMT were Avonex 28.5%, Rebif 44 µg 24.5%, Copaxone 22.5%, Betaferon 13.0%, Rebif22 µg 8.3% and Extavia 3.1%. The mean±SD overall satisfaction according to the TSQM was 68.8±18.6 and the highest overall satisfaction was reported for Rebif 22 µg (72.4±20.3) and the lowest for Extavia (61.7±23.7). In the regression analysis, rehabilitation, interference with social life, pain on injection and number of MS treatments received were significantly associated with a decrease in overall TSMQ score. A small but significant negative correlation was found between EDSS scores and TSMQ scores (rho = -0.11, p = 0.02) and effectiveness (rho = -0.17, p<0.001). A perceived inconvenience of injections was reflected by the stated preference of 83% for once-daily oral treatment over other administration routes. CONCLUSIONS: Patients on stable injectable DMT therapy were reasonably satisfied with their treatment. Our results suggest that the main source of dissatisfaction with the current treatment is the inconvenience of the administration regimen.

Vitamin D receptor gene is epigenetically altered and transcriptionally up-regulated in multiple sclerosis.

OBJECTIVE: Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS) and poor outcome. However, the specific role that vitamin D plays in MS still remains unknown. In order to identify potential mechanisms underlying vitamin D effects in MS, we profiled epigenetic changes in vitamin D receptor (VDR) gene to identify genomic regulatory elements relevant to MS pathogenesis. METHODS: Human T cells derived from whole blood by negative selection were isolated in a set of 23 relapsing-remitting MS (RRMS) patients and 12 controls matched by age and gender. DNA methylation levels were assessed by bisulfite cloning sequencing in two regulatory elements of VDR. mRNA levels were measured by RT-qPCR to assess changes in VDR expression between patients and controls. RESULTS: An alternative VDR promoter placed at exon 1c showed increased DNA methylation levels in RRMS patients (median 30.08%, interquartile range 19.2%) compared to controls (18.75%, 9.5%), p-value<0.05. Moreover, a 6.5-fold increase in VDR mRNA levels was found in RRMS patients compared to controls (p-value<0.001). CONCLUSIONS: An alternative promoter of the VDR gene shows altered DNA methylation levels in patients with multiple sclerosis, and it is associated with VDR mRNA upregulation. This locus may represent a candidate regulatory element in the genome relevant to MS pathogenesis.

Protein degradation in a LAMP-2-deficient B-lymphoblastoid cell line from a patient with Danon disease.

Danon disease, a condition characterized by cardiomyopathy, myopathy, and intellectual disability, is caused by mutations in the LAMP-2 gene. Lamp-2A protein, generated by alternative splicing from the Lamp-2 pre-mRNA, is reported to be the lysosomal membrane receptor essential for the chaperone-mediated autophagic pathway (CMA) aimed to selective protein targeting and translocation into the lysosomal lumen for degradation. To study the relevance of Lamp-2 in protein degradation, a lymphoblastoid cell line was obtained by EBV transformation of B-cells from a Danon patient. The derived cell line showed no significant expression of Lamp-2 protein. The steady-state mRNA and protein levels of alpha-synuclein, IΚBα, Rcan1, and glyceraldehyde-3-phosphate dehydrogenase, four proteins reported to be selective substrates of the CMA pathway, were similar in control and Lamp-2-deficient cells. Inhibition of protein synthesis showed that the half-life of alpha-synuclein, IΚBα, and Rcan1 was similar in control and Lamp-2-deficient cells, and its degradation prevented by proteasome inhibitors. Both in control and Lamp-2-deficient cells, induction of CMA and macroautophagy by serum and aminoacid starvation of cells for 8h produced a similar decrease in IΚBα and Rcan1 protein levels and was prevented by the addition of lysosome and autophagy inhibitors. In conclusion, the results presented here showed that Lamp-2 deficiency in human lymphoblastoid cells did not modify the steady-state levels or the degradation of several protein substrates reported as selective substrates of the CMA pathway.

Fingolimod: efectividad y seguridad en la práctica clínica habitual. Estudio observacional, retrospectivo y multicéntrico en Navarra, Gipuzkoa y La Rioja / Fingolimod: effectiveness and safety in routine clinical practice. An observational, retrospective, multi-centre study in Navarra, Gipuzkoa and La Rioja

Objetivo. Evaluar la efectividad y seguridad del fingolimod en la práctica clínica en las regiones de Navarra, Gipuzkoa y La Rioja. Pacientes y métodos. Estudio retrospectivo y multicéntrico de pacientes con esclerosis múltiple recurrente tratados con fingolimod, siguiendo la ficha técnica. Se evaluó la tasa anualizada de brotes (TAB), el porcentaje de pacientes libres de brotes, la discapacidad usando la escala expandida del estado de discapacidad (EDSS) y el porcentaje de pacientes sin lesiones captantes de gadolinio. Resultados. Un total de 113 pacientes fueron tratados con fingolimod: el 6%, naïve, y el 58% y 35%, pacientes tratados previamente con inmunomodulador y natalizumab, respectivamente. El fingolimod disminuyó la TAB tras el primer (67%; 1 a 0,3; p < 0,0001) y segundo (89%; 1 a 0,1; p < 0,0001) año de tratamiento, y aumentó así el porcentaje de pacientes libres de brotes durante el tratamiento. La EDSS basal fue 3 y después del tratamiento con fingolimod fue 2,5 en ambos años. El porcentaje de pacientes sin lesiones captantes de gadolinio tras el primer año de tratamiento fue del 77%. Resultados similares se observaron en los pacientes naïve y en los tratados previamente con inmunomodulador. En los pacientes tratados previamente con natalizumab no se observaron cambios tras el tratamiento. Conclusiones. El uso del fingolimod en la práctica clínica mostró una efectividad similar a la eficacia observada en ensayos clínicos. No hubo cambios en la TAB al cambiar desde natalizumab, y sólo un paciente tras suspender el natalizumab presentó ‘rebrote’. El fingolimod se comporta como un fármaco seguro, con escasos efectos adversos y con un bajo porcentaje de abandonos (AU)

Aim. To evaluate the effectiveness and safety of fingolimod in clinical practice in Navarra, Gipuzkoa and La Rioja regions. Patients and methods. We conducted a retrospective multi-centre study with recurrent multiple sclerosis patients treated with fingolimod, following the product data sheet. The following data were evaluated: annualised relapse rate (ARR), percentage of patients free from relapses, disability using the Expanded Disability Status Scale (EDSS) and the percentage of patients without gadolinium-enhancing lesions. Results. A total of 113 patients were treated with fingolimod: 6% were naïve, and 58% and 35% were patients previously treated with an immunomodulator and natalizumab, respectively. Fingolimod lowered the ARR after the first (67%; 1 to 0.3; p < 0.0001) and second (89%; 1 to 0.1; p < 0.0001) years of treatment, and thus the number of patients free from relapses during the treatment increased. The baseline EDSS was 3 and after treatment with fingolimod was 2.5 in both years. The percentage of patients without gadolinium-enhancing lesions after the first year of treatment was 77%. Similar results were observed in naïve patients and in those previously treated with an immunomodulator. In patients previously treated with natalizumab no changes were observed following the treatment. Conclusions. The use of fingolimod in clinical practice showed an effectiveness similar to that observed in clinical trials. There were no changes in the ARR after changing from natalizumab, and only one patient presented a ‘relapse’ after withdrawal of natalizumab. Fingolimod acts like a safe drug, with scarce side effects and a low percentage of drop-outs (AU)

Analysis of prognostic factors associated with longitudinally extensive transverse myelitis.

OBJECTIVE: The aim of this study is to report the clinical profile and outcome of longitudinally extensive transverse myelitis (LETM). METHODS: We prospectively studied adult patients who presented with LETM from January 2008 to December 2011. Information on demographic, clinical course, magnetic resonance imaging (MRI) and outcome was collected. HLA-DRB1 genotype was compared with those of 225 normal controls and patients with MS (228) and neuromyelitis optica (NMO) (22). RESULTS: In total, 23 patients (16 female) with a median age of 44.5 years (range: 20-77 years) were included. Most (74%) had moderate-severe disability at nadir (48% non-ambulatory), normal/non-multiple sclerosis (MS) brain MRI (96%) and a median MRI cord lesion of 5 vertebral segments (range: 3-19). Laboratory analysis showed cerebrospinal fluid pleocytosis (45%), NMO-IgG (9%), antinuclear antibodies (70%), and genotype HLA-DRB1*13 (57%). The frequency of DRB1*13 genotype was higher compared with controls (p=0.002), MS (p=0.001) and NMO (p=0.003) patients. After a median follow-up of 32 months, one patient converted to MS, two had relapsing LETM with NMO-IgG, and 20 remained as idiopathic with recurrences in four (20%). Twelve (52%) patients recovered with minimal disability (Expanded Disability Status Scale (EDSS) ≤2.5) and three (13%) remained wheelchair dependent. Disability at nadir was associated with the final outcome and extension of the spinal cord lesion with risk of recurrence. Recurrence was not associated with worse outcome. CONCLUSIONS: Inflammatory LETM is mostly idiopathic with a good outcome. It includes a relatively homogenous group of patients with an overrepresentation of the HLA-DRB1*13 genotype. EDSS at nadir is a predictor of the final outcome and extension of the myelitis of the recurrence risk.

Myasthenia gravis: sleep quality, quality of life, and disease severity.

INTRODUCTION: There is much research on quality of life in myasthenia gravis (MG), and its relationship to disease severity is well-established. However, evidence regarding sleep disturbance in MG is inconclusive. METHODS: To evaluate sleep and quality of life among clinically stable MG patients, 54 subjects were investigated by means of the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and 15-Item-Quality-Of-Life Instrument for MG (MG-QOL15). RESULTS: A pathological PSQI score, which was observed in 59% of patients, was increased in subjects with active disease compared with patients in clinical remission [odds ratio = 4.3; confidence interval 95% (1.0-17.6); P = 0.04]. We found a relationship between PSQI and MG-QOL15 scores in patients with clinically active disease (r = 0.62; P < 0.001). CONCLUSIONS: Our study highlights the high prevalence of sleep disturbance among MG patients. Disease severity may be considered to be a MG-specific risk factor for patient-reported sleep disturbance. The MG-QOL15 and PSQI should be used to estimate the impact of the disease on sleep and quality of life.