Satisfaction and experiences of patients taking fingolimod and involved in a pharmacy-based patient support program in Switzerland - a qualitative study.

BACKGROUND: Fingolimod is an oral multiple sclerosis drug that is considered a specialty drug due to its high cost and safety issues. The Fingolimod Patient Support Program (F-PSP) is a specialty pharmacy service developed to ensure the responsible use of fingolimod by promoting patient safety and medication adherence. This study aims to explore the satisfaction, experiences and perceptions regarding the F-PSP among patients currently involved in this program or recently withdrawn. METHODS: A qualitative study was conducted via individual, face-to-face semistructured interviews with patients involved in the F-PSP. The interviews were audio-recorded, transcribed verbatim, coded and analyzed via thematic content analysis. RESULTS: The main themes identified from the interviews (n = 17) were overall perception of the F-PSP, perception of the pharmacist-led consultations, perception of the tools (electronic monitor and drug intake graph), reasons to participate or potentially withdraw, and suggestions for improvements. Participants perceived the F-PSP as a reassuring support that complemented their medical care, providing a more human, personalized and person-centered approach than usual pharmacy care. Pharmacist-led consultations were valued for the medication-related and holistic support they provided. The importance of the pharmacist's attitude was emphasized. The electronic monitor was valued for promoting daily medication adherence and allowing the involvement of relatives, which reassured participants and their relatives. The participants appreciated the drug intake graph because it provided an objective overview of medication adherence, thereby reassuring, rewarding, and motivating them. The main reason to join the program was to be supported, especially with respect to medication adherence. CONCLUSIONS: Participants were satisfied with the F-PSP, each for different reasons. Their feedback enabled the identification of measures for the optimization of the F-PSP and should facilitate its dissemination and transfer to other drugs/diseases/populations. Essential elements of generic pharmacist-led patient support programs considered valuable from the patients' perspective were identified.

[Neurology]. / Neurologie.

Ocrelizumab (Ocrevus), an anti-CD20 monoclonal antibody, has been approved for the treatment of multiple sclerosis. Eculizumab (Soliris) has been approved in several countries for refractory forms of generalized seropositive severe myasthenia gravis. A form of gene therapy, patisiran, has shown positive results in transthyretin familial amyloidosis. In the treatment of headaches, particularly migraines, non-pharmacological approaches have shown some interesting results. The criteria for Lewy body dementia have been revised. Generic use of lamotrigine does not result in recrudescence of epileptic seizures or adverse effects.

L'ocrélizumab (Ocrevus), un anticorps monoclonal anti-CD20, a été homologué dans le traitement de la sclérose en plaques. L'éculizumab (Soliris) a été approuvé dans plusieurs pays pour les formes réfractaires de myasthénie grave généralisée séropositive. Une forme de thérapie génique, le patisiran a montré des résultats positifs dans l'amyloïdose à transthyrétine. Dans le traitement des céphalées, en particulier des migraines, les approches non pharmacologiques ont montré quelques avancées. Les critères de la démence à corps de Lewy ont été révisés. L'utilisation de génériques de la lamotrigine n'engendre pas de recrudescence de crises épileptiques ni d'effets indésirables.

Progressive multifocal leukoencephalopathy in two natalizumab-treated stepsisters: An intriguing coincidence.

BACKGROUND: Natalizumab, a treatment used in multiple sclerosis (MS), is associated with cases of progressive multifocal leukoencephalopathy (PML). OBJECTIVE: We describe two cases of PML in related but not genetically apparented natalizumab-treated MS patients who are stepsisters. Reported cases/outcomes: While Patient 1 developed PML, Patient 2 was on natalizumab and had contacts with Patient 1. Patient 2 was diagnosed with PML 5 months after Patient 1. CONCLUSION: The clinical and temporal data highly suggest that there was JC virus (JCV) transmission from one patient to the other with development of PML as primo-infection in Patient 2.

Increased ex vivo antigen presentation profile of B cells in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is thought to be T cell mediated but the mechanisms eliciting such a dysregulated adaptative immune response remain enigmatic. OBJECTIVE: To examine the activation profile of antigen-presenting cells (APCs) in MS. METHODS: A total of 98 study subjects were enrolled including patients suffering from relapsing-remitting, secondary- and primary-progressive (PP) MS, other inflammatory neurological diseases, and healthy controls. Blood monocytes and B cells were stimulated using specific ligands of toll-like receptors (TLRs) or inflammasomes or Epstein-Barr virus (EBV) particles. Their activation profile was determined before or after stimulation by flow cytometry (CD40, CD80, CD83, CD86, and human leukocyte antigen-antigen D related (HLA-DR)) and Luminex assay, measuring the concentration of eight cytokines in culture supernatants. Differences among groups were assessed in a linear model framework. RESULTS: We demonstrate that relapsing MS patients exhibit an increased expression of HLA-DR and CD40 ex vivo, mostly at the surface of B cells. Specific stimulations of TLR or inflammasomes enhance the expression of components of the immunological synapse and the cytokine secretion but without differences between categories of study subjects. CONCLUSION: These data suggest that the activation profile of B cells is increased in MS. However, the perception of the danger signal by B lymphocytes and monocytes does not seem to be different in MS patients as compared to control subjects.

[Neurology]. / Neurologie.

Aducanumab reduces the burden of amyloid plaques in Alzheimer's disease, with significant improvement of clinical scores. Endovascular thrombectomy is recommended in patients with acute stroke with proximal occlusion of the anterior circulation. CGRP antagonists and botulinum toxin are effective in migraine. ZIKA virus infection has been linked to the Guillain-Barré syndrome. Edaravone has been approved for amyotrophic lateral sclerosis. Two monoclonal antibodies (ocrelizumab and daclizumab) and siponimod show positive results in multiple sclerosis. Thalamotomy of ventral intermediate nucleus (by gamma-knife or by magnetic resonance-guided focused ultrasound) is effective in drug-resistant essential tremor. The dose-dependent risk of foetal malformations associated with valproate and topiramate is confirmed.

L'aducanumab réduit la présence de plaques amyloïdes dans la maladie d'Alzheimer, avec amélioration significative des scores cliniques. Dans l'AVC aigu, la thrombectomie endovasculaire est recommandée en présence d'une occlusion proximale de la circulation antérieure. La toxine botulinique est efficace dans la migraine chronique. L'infection à virus Zika est associée au syndrome de Guillain-Barré. L'édaravone a été approuvé pour la sclérose latérale amyotrophique. Deux anticorps monoclonaux (ocrélizumab et daclizumab) et le siponimod montrent des résultats positifs dans la sclérose en plaques. La thalamotomie du noyau ventral intermédiaire par gamma-knife et par ultrasons focalisés guidés par résonance magnétique est efficace dans le tremblement pharmaco-résistant. Le risque dose-dépendant de malformations fœtales liées au valproate et au topiramate est confirmé.

Automated detection of white matter and cortical lesions in early stages of multiple sclerosis.

PURPOSE: To develop a method to automatically detect multiple sclerosis (MS) lesions, located both in white matter (WM) and in the cortex, in patients with low disability and early disease stage. MATERIALS AND METHODS: We developed a lesion detection method, based on the k-nearest neighbor (k-NN) technique, to detect lesions as small as 0.0036 mL. This method uses the image intensity information from up to four different 3D magnetic resonance imaging (MRI) sequences (magnetization-prepared rapid gradient-echo, MPRAGE; magnetization-prepared two inversion-contrast rapid gradient-echo, MP2RAGE; 3D fluid-attenuated inversion recovery, FLAIR; and 3D double-inversion recovery, DIR), acquired on a 3T scanner. To these intensity features we added the information obtained by the spatial coordinates and tissue prior probabilities provided by the International Consortium for Brain Mapping (ICBM). Quantitative assessment was done in 39 early-stage MS patients with a "leave-one-out" cross-validation. RESULTS: The best lesion detection rate (DR) performance in WM was obtained using MP2RAGE, FLAIR, and DIR intensities (77% for lesions ≥0.0036 mL; 85% for lesions ≥0.005 mL). Similar results were obtained excluding the DIR intensity as well as when using only MPRAGE and FLAIR (DR = 75%, P = 0.5720). However, the combination of FLAIR with DIR and MP2RAGE appeared to be the best for detecting cortical lesions (DR = 62%), compared to the other combination of sequences (P < 0.001). CONCLUSION: For WM lesion detection, similar results were observed when only conventional clinical sequences (FLAIR, MPRAGE) were used compared to a combination of conventional and "advanced" sequences (MP2RAGE, DIR). Cortical lesion detection increased significantly when "advanced" sequences were used. J. Magn. Reson. Imaging 2015. J. Magn. Reson. Imaging 2016;43:1445-1454.

Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity.

BACKGROUND/OBJECTIVES: Neurofilament light chain (NfL) levels in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients correlate with the degree of neuronal injury. To date, little is known about NfL concentrations in the serum of relapsing remitting multiple sclerosis (RRMS) patients and their relationship with CSF levels and magnetic resonance imaging (MRI) measures of disease severity. We aimed to validate the quantification of NfL in serum samples of RRMS, as a biofluid source easily accessible for longitudinal studies. METHODS: A total of 31 RRMS patients underwent CSF and serum sampling. After a median time of 3.6 years, 19 of these RRMS patients, 10 newly recruited RRMS patients and 18 healthy controls had a 3T MRI and serum sampling. NfL concentrations were determined by electrochemiluminescence immunoassay. RESULTS: NfL levels in serum were highly correlated to levels in CSF (r = 0.62, p = 0.0002). Concentrations in serum were higher in patients than in controls at baseline (p = 0.004) and follow-up (p = 0.0009) and did not change over time (p = 0.56). Serum NfL levels correlated with white matter (WM) lesion volume (r = 0.68, p < 0.0001), mean T1 (r = 0.40, p = 0.034) and T2* relaxation time (r = 0.49, p = 0.007) and with magnetization transfer ratio in normal appearing WM (r = -0.41, p = 0.029). CONCLUSION: CSF and serum NfL levels were highly correlated, and serum concentrations were increased in RRMS. Serum NfL levels correlated with MRI markers of WM disease severity. Our findings further support longitudinal studies of serum NfL as a potential biomarker of on-going disease progression and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.

Multicontrast connectometry: a new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. METHODS: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. RESULTS: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. CONCLUSION: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage.

Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes.

BACKGROUND: Increasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS. METHODS: IL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood. Identification of the IL-22 receptor subunit, IL-22R1, was performed by immunohistochemistry and immunofluorescence in human brain tissues and human primary astrocytes. The role of IL-22 on human primary astrocytes was evaluated using 7-AAD and annexin V, markers of cell viability and apoptosis, respectively. RESULTS: In a cohort of 141 MS patients and healthy control (HC) subjects, we found that serum levels of IL-22 were significantly higher in relapsing MS patients than in HC but also remitting and progressive MS patients. Monocytes and monocyte-derived dendritic cells contained an enhanced expression of mRNA coding for IL-22BP as compared to HC. Using immunohistochemistry and confocal microscopy, we found that IL-22 and its receptor were detected on astrocytes of brain tissues from both control subjects and MS patients, although in the latter, the expression was higher around blood vessels and in MS plaques. Cytometry-based functional assays revealed that addition of IL-22 improved the survival of human primary astrocytes. Furthermore, tumor necrosis factor α-treated astrocytes had a better long-term survival capacity upon IL-22 co-treatment. This protective effect of IL-22 seemed to be conferred, at least partially, by a decreased apoptosis. CONCLUSIONS: We show that (1) there is a dysregulation in the expression of IL-22 and its antagonist, IL-22BP, in MS patients, (2) IL-22 targets specifically astrocytes in the human brain, and (3) this cytokine confers an increased survival of the latter cells.

A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.

BACKGROUND: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. OBJECTIVE: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. METHODS: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. RESULTS: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. CONCLUSION: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.

[News in neurology 2014]. / Neurologie.

In 2014, breastfeeding during maternal antiepileptic therapy seems to be safe for the children and can be recommended. Intravenous thrombolysis by Alteplase improves the outcome after a stroke if administered within 4.5 hours and it is also recommended in elderly population over 80 years. ProSavin genic therapy for Parkinson disease is under investigation. The Transcranial Magnetic Stimulation (TMS) has an analgesic effect in neuropathic pain as well as an antidepressant effect. Antagonists of calcitonin gene-related peptide can have a beneficial role in migraine prevention. Diagnostic biomarker panels for Alzheimer disease are under investigation. Oral teriflunomide and dimethyl fumarate (BG-12) for relapsing multiple sclerosis treatment are now available in Switzerland.

Natalizumab treatment alters the expression of T-cell trafficking marker LFA-1 α-chain (CD11a) in MS patients.

OBJECTIVE: To determine the long-term effect of natalizumab (NTZ) treatment on the expression of integrins and chemokine receptors involved in the migration of T cells towards the central nervous system (CNS). METHODS: We drew the blood of 23 patients just before starting NTZ therapy and every 12 months thereafter, for up to 48 months of treatment. We assessed the ex-vivo expression of phenotype markers (CCR7 and CD45RA), CNS-addressing integrins (CD11a, CD49d and CD29) and chemokine receptors (CXCR3 and CCR6) in CD4+ or CD8+ T-cell subsets by flow cytometry. RESULTS: As compared to the pre-NTZ values, there was a marked increase in central memory (CCR7+/CD45RA-) CD4+ T cells and in effector memory (CCR7-/CD45RA-) CD8+ T cells at 12 and 24 months. In addition to an expected downregulation of both VLA-4 subunits (CD49d/CD29), we also found decreased T-cell expression of CXCR3 at 12 months, and of CD11a (LFA-1 αL subunit) at 12 months, but mostly at 24 months of NTZ treatment. CONCLUSION: Our data show a nadir of CD11a expression at 2 years of NTZ treatment, at the peak of incidence of progressive multifocal leukoencephalopathy (PML), indirectly suggesting that a lack of these molecules may play a role in the onset of PML in NTZ-treated patients.

HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis.

It was hypothesized that the EBV-specific CD8(+) T cell response may be dysregulated in multiple sclerosis (MS) patients, possibly leading to a suboptimal control of this virus. To examine the CD8(+) T cell response in greater detail, we analyzed the HLA-A2-, HLA-B7-, and HLA-B8-restricted EBV- and CMV-specific CD8(+) T cell responses in a high number of MS patients and control subjects using tetramers. Content in cytolytic granules, as well as cytotoxic activity, of EBV- and CMV-specific CD8(+) T cells was assessed. We found that MS patients had a lower or a higher prevalence of HLA-A2 and HLA-B7, respectively. Using HLA class I tetramers in HLA-B7(+) MS patients, there was a higher prevalence of MS patients with HLA-B*0702/EBV(RPP)-specific CD8(+) T cells ex vivo. However, the magnitude of the HLA-B*0702/EBV(RPP)-specific and HLA-B*0702/CMV(TPR)-specific CD8(+) T cell response (i.e., the percentage of tetramer(+) CD8(+) T cells in a study subject harboring CD8(+) T cells specific for the given epitope) was lower in MS patients. No differences were found using other tetramers. After stimulation with the HLA-B*0702/EBV(RPP) peptide, the production of IL-2, perforin, and granzyme B and the cytotoxicity of HLA-B*0702/EBV(RPP)-specific CD8(+) T cells were decreased. Altogether, our findings suggest that the HLA-B*0702-restricted viral (in particular the EBV one)-specific CD8(+) T cell response is dysregulated in MS patients. This observation is particularly interesting knowing that the HLA-B7 allele is more frequently expressed in MS patients and considering that EBV is associated with MS.

[News in neurology 2013]. / Neurologie.

In 2013, perampanel is approved as an add-on treatment for generalised and focal seizures in pharmaco-resistant epilepsy. New anticoagulants are superior to antivitamin K in stroke secondary prevention in case of atrial fibrillation. DBS remains a valid therapeutic option for advanced Parkinson's disease. Intranasal ketamine seems to reduce the intensity of severe migraine aura. High concentrations of topic capsaicin improve post-herpetic neuralgia. In Alzheimer's disease, statins might deteriorate cognitive functions. Oral immuno-modifing treatments for relapsing remitting multiple sclerosis have shown to slow cerebral atrophy progression at two years.

Principal components of functional connectivity: a new approach to study dynamic brain connectivity during rest.

Functional connectivity (FC) as measured by correlation between fMRI BOLD time courses of distinct brain regions has revealed meaningful organization of spontaneous fluctuations in the resting brain. However, an increasing amount of evidence points to non-stationarity of FC; i.e., FC dynamically changes over time reflecting additional and rich information about brain organization, but representing new challenges for analysis and interpretation. Here, we propose a data-driven approach based on principal component analysis (PCA) to reveal hidden patterns of coherent FC dynamics across multiple subjects. We demonstrate the feasibility and relevance of this new approach by examining the differences in dynamic FC between 13 healthy control subjects and 15 minimally disabled relapse-remitting multiple sclerosis patients. We estimated whole-brain dynamic FC of regionally-averaged BOLD activity using sliding time windows. We then used PCA to identify FC patterns, termed "eigenconnectivities", that reflect meaningful patterns in FC fluctuations. We then assessed the contributions of these patterns to the dynamic FC at any given time point and identified a network of connections centered on the default-mode network with altered contribution in patients. Our results complement traditional stationary analyses, and reveal novel insights into brain connectivity dynamics and their modulation in a neurodegenerative disease.

MOBP-specific cellular immune responses are weaker than MOG-specific cellular immune responses in patients with multiple sclerosis and healthy subjects.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Myelin oligodendrocyte glycoprotein (MOG) and myelin oligodendrocyte basic protein (MOBP) were both shown to be highly encephalitogenic in animal models of MS. In contrast, the association of MOG- and MOBP-specific humoral or cellular immune responses and MS in humans is far less established. In this study, we sought to analyse MOG- and MOBP-specific T-cell responses in a large cohort of patients with various stages of the disease. Patients with other neurological diseases and healthy subjects were enrolled to serve as control study subjects. We determined the proliferation and the secretion of IFN-γ secretion in our cohort. We found that MOG-specific T-cell responses were higher and more frequent as compared to MOBP-specific ones. However, both MS patients and control study subjects had similar myelin-specific T-cell responses at the periphery, thus calling for more precise studies at CNS level.

Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity.

Multiple sclerosis (MS), a variable and diffuse disease affecting white and gray matter, is known to cause functional connectivity anomalies in patients. However, related studies published to-date are post hoc; our hypothesis was that such alterations could discriminate between patients and healthy controls in a predictive setting, laying the groundwork for imaging-based prognosis. Using functional magnetic resonance imaging resting state data of 22 minimally disabled MS patients and 14 controls, we developed a predictive model of connectivity alterations in MS: a whole-brain connectivity matrix was built for each subject from the slow oscillations (<0.11 Hz) of region-averaged time series, and a pattern recognition technique was used to learn a discriminant function indicating which particular functional connections are most affected by disease. Classification performance using strict cross-validation yielded a sensitivity of 82% (above chance at p<0.005) and specificity of 86% (p<0.01) to distinguish between MS patients and controls. The most discriminative connectivity changes were found in subcortical and temporal regions, and contralateral connections were more discriminative than ipsilateral connections. The pattern of decreased discriminative connections can be summarized post hoc in an index that correlates positively (ρ=0.61) with white matter lesion load, possibly indicating functional reorganisation to cope with increasing lesion load. These results are consistent with a subtle but widespread impact of lesions in white matter and in gray matter structures serving as high-level integrative hubs. These findings suggest that predictive models of resting state fMRI can reveal specific anomalies due to MS with high sensitivity and specificity, potentially leading to new non-invasive markers.

[Multiple sclerosis: beyong first line therapies]. / Sclérose en plaques: au-delà des traitements de première ligne.

We are currently experiencing a key period in the management of patients with relapsing remitting multiple sclerosis. The application of new criteria allows early diagnosis, thus at a stage when the available immune treatments are the most likely to show a good efficacy. The therapeutic offer is expanding but its complexity too. It is thus important, for a given patient, to assess as precisely as possible the degree of severity of his/her disease, in order to give the drug with the optimal risk/benefit ratio.

Intrathecal immune responses to EBV in early MS.

EBV has been consistently associated with MS, but its signature in the CNS has rarely been examined. In this study, we assessed EBV-specific humoral and cellular immune responses in the cerebrospinal fluid (CSF) of patients with early MS, other inflammatory neurological diseases (OIND) and non-inflammatory neurological diseases (NIND). The neurotropic herpesvirus CMV served as a control. Virus-specific humoral immune responses were assessed in 123 consecutive patients and the intrathecal recruitment of virus-specific antibodies was expressed as antibody indexes. Cellular immune responses tested in the blood of 55/123 patients were positive in 46/55. The CD8(+) CTL responses of these 46 patients were assessed in the blood and CSF using a CFSE-based CTL assay. We found that viral capsid antigen and EBV-encoded nuclear antigen-1, but not CMV IgG antibody indexes, were increased in early MS as compared with OIND and NIND patients. There was also intrathecal enrichment in EBV-, but not CMV-specific, CD8(+) CTL in early MS patients. By contrast, OIND and NIND patients did not recruit EBV- nor CMV-specific CD8(+) CTL in the CSF. Our data, showing a high EBV-, but not CMV-specific intrathecal immune response, strengthen the association between EBV and MS, in particular at the onset of the disease.

Longitudinal analysis of safety and medication adherence of patients in the Fingolimod patient support program: a real-world observational study.

The Fingolimod Patient Support Program (F-PSP) is an interprofessional specialty pharmacy service designed to ensure responsible use of fingolimod by promoting patient safety and medication adherence. This study aims to evaluate the safety and medication adherence of patients who joined the F-PSP between 2013 and 2016. Sociodemographic and medical characteristics, patient safety data (patient-reported symptoms, discontinuations due to adverse events (AEs), repeated first-dose monitoring), and medication adherence (implementation, persistence, reasons for discontinuation, influence of covariates, barriers and facilitators) were described. Sixty-seven patients joined the F-PSP. Patients reported a high frequency of symptoms. Due to AEs, 7 patients discontinued fingolimod, 3 took therapeutic breaks, and 1 reduced the regimen temporarily. Three patients repeated the first-dose monitoring. Patients had a high medication adherence over the 18-month analysis period: implementation decreased from 98.8 to 93.7%, and fingolimod persistence was 83.2% at 18 months. The patients' level of education, professional situation, and living with child(ren) influenced implementation. Patients reported more facilitators of medication adherence than barriers. The F-PSP seems valuable for supporting individual patients (ensuring responsible use of fingolimod and inviting patients for shared-decision making) and public health (indirectly gathering real-world evidence).