Evidence-based assessment of potential use of fingolimod in treatment of relapsing multiple sclerosis

Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system and represents one of the most common causes of chronic neurologic disability in young adults. All the current disease-modifying drugs are administered parenterally, and can be associated with varying degrees of injection site or infusion-related reactions. Together with other side effects, the parenteral route of administration is one of the key factors affecting adherence to therapy in multiple sclerosis. Fingolimod (FTY720) is an immunomodulator that acts on sphingosine 1-phosphate (S1P) receptors and is the first oral drug approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis. Downmodulation of S1P receptor type 1 (S1P1) slows the egress of lymphocytes from lymph nodes and recirculation to the central nervous system, reduces astrogliosis, and inhibits angiogenesis during chronic neuroinflammation. Fingolimod also regulates the migration of B cells and dendritic cells, and enhances endothelial barrier function. Results from Phase II and III clinical trials provide robust evidence of the efficacy of fingolimod in relapsing-remitting multiple sclerosis. While some caution should be exercised in terms of safety issues, the introduction of fingolimod represents a great advance in the treatment of relapsing-remitting multiple sclerosis. The pharmacologic data on fingolimod and its efficacy and safety in multiple sclerosis are reviewed in this paper

Impact of COVID-19 on multiple sclerosis care and management: Results from the European Committee for Treatment and Research in Multiple Sclerosis survey

Background: The spread of Coronavirus disease-19 (COVID-19) poses unique challenges in the management of people with multiple sclerosis (PwMS). Objectives: To collect data about the impact of COVID-19 emergency on access to care for PwMS and on MS treatment practices. Methods: Between March and July 2020, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) promoted an online survey covering patient access to care, management of relapses and visits, disease-modifying therapy (DMT) and experience with COVID-19. Results: Three-hundred and sixty neurologists from 52 countries (68% from Europe) completed the survey. 98% reported COVID-19-related restrictions. Telemedicine was adopted to overcome the limited access to care and was newly activated (73%) or widely implemented (17%). 70% reported changes in DMT management. Interferons and glatiramer were considered safe. Dimethyl fumarate, teriflunomide and fingolimod were considered safe except for patients developing lymphopenia. No modifications were considered for natalizumab in 64%, cladribine in 24%, anti-CD20 in 22% and alemtuzumab in 17%;18% (for alemtuzumab and cladribine) and 43% (for anti-CD20) considered postponing treatment. Conclusion: The ECTRIMS survey highlighted the challenges in keeping standards of care in clinical practice. Telemedicine clearly needs to be implemented. Gathering data on DMT safety will remain crucial to inform treatment decisions

Pronounced structural and functional damage in early adult pediatric-onset multiple sclerosis with no or minimal clinical disability

Pediatric-onset multiple sclerosis (POMS) may represent a model of vulnerability to damage occurring during a period of active maturation of the human brain. Whereas adaptive mechanisms seem to take place in the POMS brain in the short-medium term, natural history studies have shown that these patients reach irreversible disability, despite slower progression, at a significantly younger age than adult-onset MS (AOMS) patients. We tested for the first time whether significant brain alterations already occurred in POMS patients in their early adulthood and with no or minimal disability (n = 15) in comparison with age- and disability-matched AOMS patients (n = 14) and to normal controls (NC, n = 20). We used a multimodal MRI approach by modeling, using FSL, voxelwise measures of microstructural integrity of white matter tracts and gray matter volumes with those of intra- and internetwork functional connectivity (FC) (analysis of variance, p â\u89¤ 0.01, corrected for multiple comparisons across space). POMS patients showed, when compared with both NC and AOMS patients, altered measures of diffusion tensor imaging (reduced fractional anisotropy and/or increased diffusivities) and higher probability of lesion occurrence in a clinically eloquent region for physical disability such as the posterior corona radiata. In addition, POMS patients showed, compared with the other two groups, reduced long-range FC, assessed from resting functional MRI, between default mode network and secondary visual network, whose interaction subserves important cognitive functions such as spatial attention and visual learning. Overall, this pattern of structural damage and brain connectivity disruption in early adult POMS patients with no or minimal clinical disability might explain their unfavorable clinical outcome in the long term

Impact of Natalizumab on Cognitive Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label, Two Years Observational Study

Background and Objectives: Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years. Methods: Cognitive performances were examined by the Rao’s Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient’s selfreported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively. Results: After 1 year of treatment the percentage of CI patients decreased from 29 % (29/100) at baseline to 19 % (19/100) (p = 0.031) and the mean baseline values of CII (13.5266.85) and FSS (4.0161.63) scores were significantly reduced (10.4867.12, p,0.0001 and 3.6161.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years. Conclusions: These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performance

Relevance of brain lesion location to cognition in relapsing multiple sclerosis

OBJECTIVE: To assess the relationship between cognition and brain white matter (WM) lesion distribution and frequency in patients with relapsing-remitting multiple sclerosis (RR MS). METHODS: MRI-based T2 lesion probability map (LPM) was used to assess the relevance of brain lesion location for cognitive impairment in a group of 142 consecutive patients with RRMS. Significance of voxelwise analyses was p<0.05, cluster-corrected for multiple comparisons. The Rao Brief Repeatable Battery was administered at the time of brain MRI to categorize the MS population into cognitively preserved (CP) and cognitively impaired (CI). RESULTS: Out of 142 RRMS, 106 were classified as CP and 36 as CI. Although the CI group had greater WM lesion volume than the CP group (p = 0.001), T2 lesions tended to be less widespread across the WM. The peak of lesion frequency was almost twice higher in CI (61% in the forceps major) than in CP patients (37% in the posterior corona radiata). The voxelwise analysis confirmed that lesion frequency was higher in CI than in CP patients with significant bilateral clusters in the forceps major and in the splenium of the corpus callosum (p<0.05, corrected). Low scores of the Symbol Digit Modalities Test correlated with higher lesion frequency in these WM regions. CONCLUSIONS: Overall these results suggest that in MS patients, areas relevant for cognition lie mostly in the commissural fiber tracts. This supports the notion of a functional (multiple) disconnection between grey matter structures, secondary to damage located in specific WM areas, as one of the most important mechanisms leading to cognitive impairment in MS

Increased CD8+ T cell responses to apoptotic T cell-associated antigens in multiple sclerosis.

BACKGROUND: Here, we evaluated the hypothesis that CD8(+) T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology. METHODS: The percentage of autoreactive CD8(+) T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer(+) CD8(+) T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo. RESULTS: We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8(+) T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8(+) T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8(+) T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8(+) T cells ex vivo. CONCLUSION: Taken together, these data indicate that apoptotic epitope-specific CD8(+) T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: an Italian collaborative study

Background: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. Objective: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). Methods: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. Results: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS (p = 0.03) compared with AOMS patients.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was in part financed through an FISM (Italian Federation of Multiple Sclerosis) research grant

Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis

Objective To assess whether it is feasible to establish specific cut-off values able to discriminate 'physiological' or 'pathological' brain volume rates in patients with multiple sclerosis (MS). Methods The study was based on the analysis of longitudinal MRI data sets of patients with MS (n=206, 87% relapsing-remitting, 7% secondary progressive and 6% primary progressive) and healthy controls (HC; n=35). Brain atrophy rates were computed over a mean follow-up of 7.5 years (range 1-12) for patients with MS and 6.3 years (range 1-12.5) for HC with the SIENA software and expressed as annualised per cent brain volume change (PBVC/y). A weighted (on the follow-up length) receiver operating characteristic analysis and the area under the curve (AUC) were used for statistics. Results The weighted PBVC/y was -0.51±0.27% in patients with MS and -0.27±0.15% in HC (p&lt;0.0001). There was a significant age-related difference in PBVC/y between HC older and younger than 35 years of age ( p=0.02), but not in patients with MS (p=0.8). The cutoff of PBVC/y, as measured by SIENA that could maximise the accuracy in discriminating patients with MS from HC, was -0.37%, with 67% sensitivity and 80% specificity. According to the observed distribution, values of PBVC/y as measured by SIENA that could define a pathological range were above -0.52% with 95% specificity, above -0.46% with 90% specificity and above -0.40% with 80% specificity. Conclusions Our evidence-based criteria provide values able to discriminate the presence or absence of 'pathological' brain volume loss in MS with high specificity. Such results could be of great value in a clinical setting, particularly in assessing treatment efficacy in MS