Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date

Siponimod (BAF312) is a synthetic molecule belonging to the sphingosine-1-phosphate (S1P) modulator family, which has putative neuroprotective properties and well-characterized immunomodulating effects mediated by sequestration of B and T cells in secondary lymphoid organs. Compared to fingolimod (ie, precursor of the S1P modulators commercially available for the treatment of relapsing-remitting [RR] multiple sclerosis [MS]), siponimod exhibits selective affinity for types 1 and 5 S1P receptor, leading to a lower risk of adverse events that are mainly induced by S1P3 receptor activation, such as bradycardia and vasoconstriction. In addition, S1P1 and S1P5 receptors are expressed by neurons and glia and could mediate a possible neuroprotective effect of the drug. A Phase II clinical trial of siponimod for RR MS showed a significant effect of the active drug compared to placebo on reducing gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) after 3 months of treatment. In a recently completed Phase III trial, treatment with siponimod was associated with a significant reduction in disability progression in secondary progressive (SP) MS patients compared to placebo. In this article, current evidence supporting siponimod efficacy for SP MS is reviewed

An exploratory panel of cerebrospinal fluid biomarkers compared to standard diagnostic evaluation in initial demyelinating events suggestive of multiple sclerosis

Premessa: La diagnosi e il profilo prognostico di un primo evento demielinizzante (ED) del sistema nervoso centrale non sono di immediata definizione. La diagnosi di sclerosi multipla e di altre possibili eziologie \ue8 basata su una combinazione di criteri che spesso richiedono un lungo monitoraggio per essere soddisfatti, dal momento che singoli test con elevata sensibilit\ue0 e specificit\ue0 al momento dell\u2019evento iniziale sono limitati. I fattori predittivi di attivit\ue0 di malattia e disabilit\ue0 dopo un primo ED sono conosciuti solo in parte. Scopo dello studio: Indagare il valore di tau, proteina 14-3-3 e cistatina C come marcatori biologici liquorali di un primo ED suggestivo di sclerosi multipla, oltre al significato prognostico dei dati ricavati dalla normale valutazione diagnostica iniziale. Metodi: Il liquido cerebro-spinale (LCS) di un gruppo di soggetti con un primo ED suggestivo di sclerosi multipla \ue8 stato testato per tau, proteina 14-3-3 e cistatina C. Inoltre, sono stati raccolti dati clinici, neurofisiologici, di risonanza magnetica e dell\u2019analisi liquorale standard. Per confronto, sono stati analizzati anche campioni di LCS di pazienti con neuromielite ottica (NMO) o sindromi correlate, mielite trasversa acuta idiopatica (MTAi), malattia di Creutzfeldt-Jacob (CJ) e patologie prive di una componente neuro-infiammatoria o neurodegenerativa nota (non NIND). I marcatori liquorali sono stati testati sia in termini di significato diagnostico che prognostico. Nei casi di primo ED \ue8 stato analizzato anche il valore predittivo delle variabili cliniche, neurofisiologiche e di risonanza magnetica. Per l\u2019analisi prognostica sono stati individuati i seguenti esiti clinici di interesse: recupero del primo ED, recidiva, conversione in sclerosi multipla, livello di disabilit\ue0 neurologica (punteggio EDSS) raggiunto nel corso dell\u2019osservazione clinica. Risultati: Sono stati inclusi nello studio 46 pazienti con un primo ED, 6 con NMO, 6 con MTAi, 8 con malattia di CJ e 11 con patologie non NIND. I soggetti con NMO o MTAi avevano livelli di tau significativamente pi\uf9 elevati sia rispetto ai casi con primo ED sia rispetto ai controlli con patologie non NIND, anche se inferiori rispetto ai pazienti con malattia di CJ. I casi con primo ED, NMO e MTAi sono risultati positivi alla proteina 14-3-3 pi\uf9 frequentemente rispetto ai soggetti con patologie non NIND, sebbene una franca positivit\ue0 alla 14-3-3 sia stata osservata molto pi\uf9 spesso nei pazienti con malattia di CJ. La concentrazione liquorale di cistatina C non differiva tra casi con primo ED, NMO, MTAi e patologie non NIND, ma era significativamente pi\uf9 elevata nei pazienti con malattia di CJ rispetto agli altri gruppi, con l\u2019eccezione del gruppo NMO/MTAi. Dopo un\u2019osservazione mediana di 6,7 anni (1,5-15,3), 39 casi con primo ED sono evoluti in sclerosi multipla, mentre 7 sono rimasti monofasici. Tau, 14-3-3 e cistatina C non sono risultate correlate con la gravit\ue0 e il recupero del primo ED, con il rischio di conversione in sclerosi multipla n\ue9 con la successiva disabilit\ue0 e il tasso di ricadute nei pazienti con sclerosi multipla. L\u2019esordio clinico grave era associato in modo indipendente al recupero incompleto del primo ED; la presenza di almeno tre lesioni periventricolari alla risonanza magnetica iniziale era predittiva di recidiva e conversione in sclerosi multipla; mentre il coinvolgimento piramidale all\u2019esordio e il numero di recidive correlavano con la disabilit\ue0 a lungo termine nei casi di sclerosi multipla. Conclusioni: La combinazione dei tre marcatori studiati ha fornito indicazioni sui processi patologici alla base di distinte malattie del sistema nervoso centrale. La tau liquorale ha dimostrato una potenziale utilit\ue0 diagnostica nel differenziare i casi di primo ED suggestivo di sclerosi multipla dai casi di NMO/MTAi. Sebbene il pannello di marcatori proposto non abbia dimostrato un valore predittivo nei soggetti con un primo ED, i dati clinici, neurofisiologici e di risonanza magnetica si confermano in questo studio indicatori prognostici utili in questo gruppo di pazienti.Background: The diagnosis and the prognostic profile of an initial demyelinating event (IDE) of the central nervous system are not straightforward. The diagnosis of multiple sclerosis (MS) and other IDE etiologies stands on a combination of criteria often requiring a long follow-up to be fulfilled, since single tests with high sensitivity and specificity at the time of IDE presentation are limited. Predictors of disease activity and disability after an IDE are only partially known. Study aim: To investigate the value of tau, 14-3-3 protein and cystatin C as cerebrospinal fluid (CSF) biomarkers of IDEs suggestive of MS, in addition to the prognostic information provided by standard diagnostic evaluation. Methods: CSF samples of a group of subjects with IDEs suggestive of MS were tested for tau, 14-3-3 protein and cystatin C. Clinical, MRI, neurophysiological, and standard CSF analysis data were also collected. For comparison, CSF from patients with neuromyelitis optica (NMO) spectrum disorders, idiopathic acute transverse myelitis (iATM), Creutzfeldt-Jacob disease (CJD) and non-inflammatory/non-neurodegenerative disorders (NINDDs) was also analyzed. CSF biomarkers were tested for diagnostic and prognostic significance. The predictive value of clinical, MRI, and neurophysiological variables was also analyzed in IDE cases. The outcomes of interest for prognostic analysis were: IDE recovery, relapse occurrence, conversion to MS, and subsequent disability level (EDSS score). Results: Forty-six patients with MS-like IDEs, 6 with NMO, 6 with iATM, 8 with CJD and 11 with NINDDs were included. NMO/iATM patients showed significantly higher tau levels compared to both NINDDs and IDEs, even if lower compared to CJD cases. IDE and NMO/iATM patients tested 14-3-3 positive more frequently than NINDDs, although frank 14-3-3 presence was seen much more often in CJD cases. CSF cystatin C concentration did not differ between IDE, NMO/iATM, and NINDDs cases, but was significantly higher in CJD compared to other groups, with the exception of NMO/iATM cases. After a median follow-up of 6.7 (1.5-15.3) years, 39 IDE patients converted to MS, while 7 remained monophasic. CSF tau, 14-3-3 and cystatin C were not correlated to IDE severity and recovery, to risk of MS conversion, or to subsequent disability and relapse rate in MS patients. Severe clinical onset was independently associated with incomplete IDE recovery, the presence of at least 3 periventricular lesions on baseline MRI with relapse risk and conversion to MS, while initial pyramidal involvement and number of relapses with long-term disability in MS cases. Conclusions: The three combined biomarkers provided indications about the underlying pathological processes in distinct CNS disorders. CSF tau showed potential diagnostic utility in differentiating between IDEs suggestive of MS and NMO/iATM. Although the proposed CSF biomarkers panel seems to lack predictive value for IDEs, clinical, MRI and neurophysiological parameters are here confirmed as useful prognostic indicators in this group of patients

Editorial: Bridging the gap between basic neurosciences and clinical neuroimmunology

[no abstract available

Insights for fostering resilience in young adults with multiple sclerosis in the aftermath of the COVID-19 emergency: an Italian survey

Objective: Recent evidence has demonstrated that the COVID-19 pandemic is taking a toll on the mental health of the general population. The psychological consequences might be even more severe for patients with special healthcare needs and psychological vulnerabilities due to chronic diseases, such as multiple sclerosis (MS). Thus, we aimed to explore the psychological impact of this pandemic and of the subsequent healthcare service changes on young adults with MS living in Italy and to examine their coping strategies and preferences regarding psychological support in the aftermath of the pandemic. Methods: Data were collected using a cross-sectional, web-based survey advertised on social networks. We report both quantitative (descriptive statistics, t-tests, and one-way ANOVA) and qualitative data (inductive content analysis). Results: Two hundred and forty-seven respondents (mean age 32 \ub1 7 years), mainly with relapsing-remitting MS, from all Italian regions participated. Participants felt more worried, confused, sad, and vulnerable because of the disease "during" the pandemic in comparison to their self-evaluation of the period "before" the COVID-19 outbreak. Similarly, their perception of control over MS decreased "during" the pandemic in comparison to the retrospective evaluation of the period "before" the COVID-19 outbreak (p < 0.01). Canceled/postponed visits/exams were listed as the most frequent MS management changes, with modified/postponed pharmacological treatment representing the most stressful change. Psychological support in dealing with pandemic-related fears and improving MS acceptance and well-being was considered extremely important by almost 40% of the respondents. Different coping strategies were mentioned in the qualitative section of the survey, with social support, hobbies, and keeping busy being the most frequent ones. Conclusions: Considering the enormous impact of the pandemic on young adults with MS, we urge MS clinical centers to implement psychological support programs that address the potentially long-lasting psychological negative impact, thus fostering the therapeutic alliance that is being threatened by the infection prevention measures imposed during the pandemic, and promoting psychological resources for adaptively managing future waves of COVID-19

Clinical efficacy, safety, and tolerability of fingolimod for the treatment of relapsing-remitting multiple sclerosis

Fingolimod is a selective immunosuppressive agent approved worldwide for the treatment of relapsing-remitting multiple sclerosis (MS), a chronic and potentially disabling neurological condition. Randomized double-blind clinical trials have shown that fingolimod significantly reduces relapse rate and ameliorates a number of brain MRI measures, including cerebral atrophy, compared to both placebo and intramuscular interferon-\u3b21a. The effect on disability progression remains controversial, since one Phase III trial showed a significant benefit of treatment while two others did not. Although fingolimod has a very convenient daily oral dosing, the possibility of serious cardiac, ocular, infectious, and other rare adverse events justified the decision of the European Medicines Agency to approve the drug as a second-line treatment for MS patients not responsive to first-line therapy, or those with rapidly evolving course. In the United States, fingolimod is instead authorized as a first-line treatment. The aim of this review is to describe and discuss the characteristics of fingolimod concerning its efficacy, safety, and tolerability in the clinical context of multiple sclerosis management

Are Cerebrospinal Fluid Biomarkers Useful in Predicting the Prognosis of Multiple Sclerosis Patients?

Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disorder of the central nervous system (CNS). Although many advances have been made in the comprehension of its pathogenesis, the etiology is still unknown. The complexity of MS reflects in the extreme variability of the clinical manifestations and clinical course both between and within patients, in addition to immunopathological mechanisms and response to treatment. Several prognostic factors have been suggested in large scale studies, but predictions in individual cases are difficult to make. Cerebrospinal fluid (CSF) biomarkers, such as 14-3-3, tau, and cystatin C are promising sources of prognostic information with a good potential of quantitative measure, sensitivity, and reliability. However, none has shown sufficient reproducibility to be applied in clinical practice. Here we review the current literature addressing the above mentioned biomarkers as MS severity predictors at an early stage

Increase of CSF inflammatory profile in a case of highly active multiple sclerosis

BACKGROUND: Clinical and imaging follow-up coupled with cerebrospinal fluid (CSF) and possibly serum profiling could provide information on disease activity and disability evolution in multiple sclerosis patients. CASE PRESENTATION: We describe the case of a relapsing-remitting MS patient whose history was characterized by failure of several therapeutic approaches and sustained disease activity. By using a highly sensitive immunoassay methodology, we examined protein expression of 70 inflammatory/cytotoxic molecules in two consecutive paired CSF and serum samples, obtained respectively in 2006 and 2013. At disease diagnosis, elevated CSF protein levels of an inflammatory pattern, including CXCL13, CXCL12, IFNγ, TNF, sTNFR1, IL8, sCD163, APRIL, BAFF, pentraxin III and MMP2 were found compared with a group of controls. At the second lumbar puncture, sustained disease activity was accompanied by considerable (more than 2 fold changes) increase expression of most of these inflammatory molecules while no significant changes in serum inflammatory markers were detected in the two consecutive serum samples. CONCLUSIONS: Elevated CSF protein expression of pro-inflammatory mediators, possibly specifically associated to GM demyelination, could remain stable or increase over time in patients with active multiple sclerosis. We underline the role of fluid analysis in understanding the pathophysiology of the disease and providing information on possible markers of disease activity and evolution

HCV-related nervous system disorders

Chronic infection with hepatitis C virus (HCV) is associated with a wide spectrum of extrahepatic manifestations, affecting different organ systems. Neurological complications occur in a large number of patients and range from peripheral neuropathy to cognitive impairment. Pathogenetic mechanisms responsible for nervous system dysfunction are mainly related to the upregulation of the host immune response with production of autoantibodies, immune complexes, and cryoglobulins. Alternative mechanisms include possible extrahepatic replication of HCV in neural tissues and the effects of circulating inflammatory cytokines and chemokines

"If you can't control the wind, adjust your sail": tips for post-pandemic benefit finding from young adults living with multiple sclerosis. A qualitative study

The COVID-19 outbreak has impacted the wellbeing of people worldwide, potentially increasing maladaptive psychological responses of vulnerable populations. Although young adults with multiple sclerosis (yawMS) might be at greater risk of developing psychological distress linked to the pandemic, they might also be able to adapt to stress and find meaning in adverse life events. The aim of the present study was to explore benefit finding in response to the pandemic in a sample of yawMS. As part of a larger project, data were collected using a cross-sectional, web-based survey. Benefit finding was analysed using a qualitative thematic approach; descriptive and inferential statistics were performed to describe the sample and compare sub-groups. Out of 247 respondents with mostly relapsing-remitting MS, 199 (31.9 \ub1 6.97 years) reported at least one benefit. Qualitative analysis showed that during the pandemic yawMS found benefits related to three themes: personal growth, relational growth, and existential growth. No differences in benefit finding were found between age sub-groups (18-30 vs. 31-45). Participants reported a wide range of benefits, some of which seem to be specific to MS or the pandemic. Results have been transformed into tips to be introduced in clinical practice to promote resilience in yawMS through meaning making

Fostering quality of life in young adults living with multiple sclerosis: a pilot study of a co-created integrated intervention

Introduction: Multiple sclerosis (MS) is generally diagnosed at an early age, making the acceptance of this chronic disease challenging. Research dedicated to young adults with MS (YawMS) is still limited. A biopsychosocial co-created intervention for YawMS integrating social, physical and psychological activities was developed (ESPRIMO intervention) in order to improve the quality of life (QoL) and well-being. This pre-post intervention assessment study examines the feasibility of the ESPRIMO intervention and its signal of efficacy. Methods: Inclusion criteria were: age 18-45 years, MS diagnosis, Expanded Disability Status Scale score &lt; 3.5. After giving informed consent, YawMS completed a battery of questionnaires, which was repeated after the intervention. The battery included a bespoke feasibility scale, the COOP/WONCA charts, and the Short Form-12 Health Survey (SF-12). Results: Fifty-three YAwMS were enrolled and 43 (81.1%) completed the intervention. The majority of the sample positively rated the pleasantness, usefulness and feasibility of the intervention. A significant change in the COOP/WONCA "general QoL" chart (t = 3.65; p &lt; 0.01) and SF-12 mental wellbeing component (t = -3.17; p &lt; 0.01) was found. Discussion: ESPRIMO is an innovative intervention that is feasible; preliminary results show an improvement in QoL and mental wellbeing. Further studies are needed to test its efficacy and evaluate future implementation in health services.Clinical trial registration: ClinicalTrials.gov, NCT04431323