1,25(OH)2D3 Differently Modulates the Secretory Activity of IFN-DC and IL4-DC: A Study in Cells from Healthy Donors and MS Patients.

Immune mechanisms play an essential role in driving multiple sclerosis (MS) and altered trafficking and/or activation of dendritic cells (DC) were observed in the central nervous system and cerebrospinal fluid of MS patients. Interferon ß (IFNß) has been used as a first-line therapy in MS for almost three decades and vitamin D deficiency is a recognized environmental risk factor for MS. Both IFNß and vitamin D modulate DC functions. Here, we studied the response to 1,25-dihydoxyvitamin D3 (1,25(OH)2D3) of DC obtained with IFNß/GM-CSF (IFN-DC) compared to classically derived IL4-DC, in three donor groups: MS patients free of therapy, MS patients undergoing IFNß therapy, and healthy donors. Except for a decreased CCL2 secretion by IL4-DC from the MS group, no major defects were observed in the 1,25(OH)2D3 response of either IFN-DC or IL4-DC from MS donors compared to healthy donors. However, the two cell models strongly differed for vitamin D receptor level of expression as well as for basal and 1,25(OH)2D3-induced cytokine/chemokine secretion. 1,25(OH)2D3 up-modulated IL6, its soluble receptor sIL6R, and CCL5 in IL4-DC, and down-modulated IL10 in IFN-DC. IFN-DC, but not IL4-DC, constitutively secreted high levels of IL8 and of matrix-metalloproteinase-9, both down-modulated by 1,25(OH)2D3. DC may contribute to MS pathogenesis, but also provide an avenue for therapeutic intervention. 1,25(OH)2D3-induced tolerogenic DC are in clinical trial for MS. We show that the protocol of in vitro DC differentiation qualitatively and quantitatively affects secretion of cytokines and chemokines deeply involved in MS pathogenesis.

Changes in John Cunningham Virus Index in Multiple Sclerosis Patients Treated with Different Disease-Modifying Therapies.

BACKGROUND: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored. OBJECTIVE: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs. METHODS: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1). RESULTS: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index <0.90 was found to be significantly increased in the ALM group (16.7 % versus 66.7 %, p = 0.05), while the percentage of patients with JCV index >1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index <0.90 was also found (23.5 % versus 1.4 %, p = 0.0006). The mean JCV index was reduced in the RTX/OCR and ALM groups, while a significant increase was observed in the FTY group. CONCLUSION: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

Early diagnosis of secondary progressive multiple sclerosis: focus on fluid and neurophysiological biomarkers.

BACKGROUND AND AIMS: Most patients with multiple sclerosis presenting with a relapsing-remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1-2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis. METHODS: We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement. RESULTS: From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers. CONCLUSION: To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion.

Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

Changes in Anti-JCV Antibody Status in a Large Population of Multiple Sclerosis Patients Treated with Natalizumab.

INTRODUCTION: Natalizumab (NTZ) can be associated with an opportunistic infection, progressive multifocal leukoencephalopathy (PML), caused by John Cunningham virus (JCV). High titer of anti-JCV antibody (JCV index) in patients treated with NTZ for over 2 years limit it use, leading to treatment discontinuation. OBJECTIVE: Aim of the study was to investigate the JCV index changes pre, during and post NTZ treatment and describe the trend after a long period of NTZ discontinuation. METHODS: Patients with relapsing-remitting multiple sclerosis (RR-MS) treated with NTZ between 2010 and 2018 were enrolled in this retrospective-prospective observational study. Inclusion criteria were: (1) diagnosis of RR-MS according to the McDonald criteria 2010, (2) at least six NTZ administrations, (3) at least two determinations of JCV Index during the follow-up period, (4) NTZ discontinuation period for more than 6 months. JCV index was determined by STRATIFY II. There were three different timepoints: NTZ initiation (T0), NTZ discontinuation (T1) and time after NTZ suspension (T2). Seroconversion was defined as changing status of serum JCV antibody. Main outcomes were the JCV index changes and the rate of seroconversion. RESULTS: At baseline we enrolled 285 patients (208 JCV negative, 67 JCV positive, and 10 not available). There was a statistically significant increase of JCV index during NTZ treatment period (T0 vs T1, p =0.0009) and during NTZ discontinuation period (T1 vs T2, p =0.04). Patients seroconverted to a positive status more frequently during NTZ treatment than after discontinuation (p =0.008). Moreover, patients who shifted to fingolimod (FTY) as exit strategy after NTZ discontinuation, showed a statistically significant increase of JCV index. CONCLUSION: Our data confirmed that a high percentage of patients shift to or remain in a positive JCV status during NTZ treatment and after discontinuation. NTZ suspension seems not to be able to interfere on JCV status modification over an extended period. The choice of alternative treatment as exit strategy after NTZ discontinuation should be carefully considered because it could negatively influence the PML risk stratification of patients.

Deep grey matter involvement and altered sensory gating in multiple sclerosis.

BACKGROUND: Somatosensory temporal discrimination threshold (STDT) is altered in multiple sclerosis (MS). In healthy subjects (HS), voluntary movement modulates the STDT through mechanisms of subcortical sensory gating. OBJECTIVE: With neurophysiological and magnetic resonance imaging (MRI) techniques, we investigated sensory gating and sensorimotor integration in MS. METHODS: We recruited 38 relapsing-remitting multiple sclerosis (RR-MS) patients with no-to-mild disability and 33 HS. We tested STDT at rest and during index finger abductions and recorded the movement kinematics. Participants underwent a 3T MRI protocol. RESULTS: Patients exhibited higher STDT values and performed slower finger movements than HS. During voluntary movement, STDT values increased in both groups, albeit to a lesser extent in patients, while the mean angular velocity of finger movements decreased in patients alone. Patients had a smaller volume of the thalamus, pallidum and caudate nucleus, and displayed higher mean diffusivity in the putamen, pallidum and thalamus. STDT correlated with thalamic volume while mean angular velocity correlated with putaminal volume. Changes in mean angular velocity during sensorimotor integration inversely correlated with mean diffusivity in the thalamus and pallidum. Changes in STDT and velocity were associated with fatigue score. CONCLUSION: Altered STDT and sensorimotor integration are related to structural damage in the thalamus and basal ganglia in MS and likely to affect motor performance.

Exit strategies for "needle fatigue" in multiple sclerosis: a propensity score-matched comparison study.

Patients with multiple sclerosis on long-term injectable therapies may suffer from the so-called "needle fatigue", i.e., a waning commitment to continue with the prescribed injectable treatment. Therefore, alternative treatment strategies to enhance patients' adherence are warranted. In this independent, multicentre post-marketing study, we sought to directly compare switching to either teriflunomide (TFN), dimethyl fumarate (DMF), or pegylated interferon (PEG) on treatment persistence and time to first relapse over a 12-month follow-up. We analyzed a total of 621 patients who were free of relapses and gadolinium-enhancing lesions in the year prior to switching to DMF (n = 265), TFN (n = 160), or PEG (n = 196). Time to discontinuation and time to first relapse were explored in the whole population by Cox regression models adjusted for baseline variables and after a 1:1:1 ratio propensity score (PS)-based matching procedure. Treatment discontinuation was more frequent after switching to PEG (28.6%) than DMF (14.7%; hazard ratio [HR] = 0.25, p < 0.001) and TFN (16.9%; HR = 0.27, p < 0.001). We found similar results even in the re-sampled cohort of 222 patients (74 per group) derived by the PS-based matching procedure. The highest discontinuation rate observed in PEG recipient was mainly due to poor tolerability (p = 0.005) and pregnancy planning (p = 0.04). The low number of patients who relapsed over the 12-month follow-up (25 out of 621, approximately 4%) prevented any analysis on the short-term risk of relapse. This real-world study suggests that oral drugs are a better switching option than low-frequency interferon for promoting the short-term treatment persistence in stable patients who do not tolerate injectable drugs.

Cortical M1 plasticity and metaplasticity in patients with multiple sclerosis.

BACKGROUND: Previous studies on patients with Multiple Sclerosis (MS) have reported contrasting findings on cortical plasticity of the primary motor cortex and no study has yet evaluated the regulatory mechanisms of cortical plasticity (i.e., metaplasticity) in MS patients. The aim of the present study was to investigate primary motor cortex (M1) plasticity and metaplasticity in patients with MS. METHODS: Nineteen patients affected by Relapsing--Remitting MS (RR-MS) and 16 age- and sex-matched healthy controls underwent intermittent Theta Burst Stimulation (iTBS) to evaluate cortical plasticity and iTBS preceded by repetitive index finger movements to evaluate M1 metaplasticity. RESULTS: In healthy subjects MEP size significantly increased after iTBS whereas it significantly decreased when repetitive index finger movements preceded iTBS (metaplasticity) (factor PROTOCOL: p < 0.0001; PROTOCOL x TIME interaction: p = 0.001). Conversely, in MS patients MEP size mildly increased, albeit not significantly in both conditions (p > 0.05). In MS patients, percentage changes in MEP size induced by plasticity and metaplasticity protocol were significantly associated to EDSS (p = 0.001) and kinematics of index finger movements (p = 0.01). CONCLUSION: M1 plasticity and metaplasticity are both altered in MS patients. When TBS is used for therapeutic purposes, TBS protocols should be tailored according to the M1 plasticity functional reserve of each MS patient.

Secukinumab may be a valid treatment option in patients with CNS demyelination and concurrent ankylosing spondylitis: Report of two clinical cases.

The therapeutic approach to CNS demyelination associated to ankylosing spondylitis is a complex issue due to the contraindication of TNF inhibitors in demyelinating diseases. Secukinumab, a human IgG1κ monoclonal antibody that binds and inhibits IL-17A, was recently approved for the treatment of ankylosing spondylitis. We report the clinical cases of two patients affected by a CNS demyelinating disease and ankylosing spondylitis who were successfully treated with secukinumab, providing additional evidence of the feasibility of this therapeutic option when the use of TNF inhibitors is discouraged by challenging comorbidities.

Photophobia in multiple sclerosis.

BACKGROUND: Photophobia has never been investigated in MS. METHODS: In this pilot study we used photosensitivity questionnaire assessment (PAQ) to evaluate tolerability to light in 73 MS patients and 62 healthy controls. RESULTS: We identified a lower PAQ score and a higher number of photophobic subjects in MS than in controls. Moreover, clinical disability or previous optic neuritis did not predict the photosensitivity profile. CONCLUSION: Further studies to investigate the pathophysiological mechanisms underlying photophobia in MS are needed.

Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis.

OBJECTIVE: To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. METHODS: An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. RESULTS: From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. CONCLUSIONS: Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly.

Safety and Efficacy of Dimethyl Fumarate in Multiple Sclerosis: An Italian, Multicenter, Real-World Study.

BACKGROUND: Two phase III trials have demonstrated the clinical and radiological efficacy of delayed-release dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS). However, data on its safety and effectiveness in real-world practice are still limited. OBJECTIVES: The aim of our study was to explore the safety and tolerability profile of DMF in RRMS. We also tried to identify individual variables associated with better clinical and radiological outcomes. METHODS: We collected the clinical and magnetic resonance imaging (MRI) data of patients with RRMS who started DMF between 2012 and 2017 in seven MS clinics in central Italy. We first evaluated DMF discontinuation rates and the incidence of adverse events and side effects. We then assessed the annualized relapse rate (ARR), the number of patients with clinical relapses or disability worsening and the presence of radiological activity. Third, we investigated which baseline variables were associated with clinical and radiological outcomes. RESULTS: We collected data for 1089 patients with a mean on-treatment follow-up of 17 ± 8 months; 331 (30.4%) of these patients were treatment naïve. In total, 210 (19.5%) patients discontinued DMF mainly because of poor tolerability (n = 103) and disease activity (n = 63), and 166 (16.5%) patients presented with lymphopenia. The ARR reduced from 0.55 to 0.13. Mean change in Expanded Disability Status Scale (EDSS) score was 0.08 ± 0.44 per year. The occurrence of clinical and/or radiological activity during follow-up was associated with younger age [hazard ratio (HR) 0.97; p < 0.001], higher EDSS score (HR 1.18; p < 0.001), greater number of Gd-enhancing lesions at baseline scan (HR 1.14; p = 0.003) and prior exposure to MS treatments (HR 1.43; p = 0.02). CONCLUSION: This post-marketing data confirms the short-term safety, tolerability and effectiveness of DMF, supporting its use as an early treatment in MS.

Fingolimod vs dimethyl fumarate in multiple sclerosis: A real-world propensity score-matched study.

OBJECTIVE: To directly compare fingolimod (FNG) and dimethyl fumarate (DMF) on no evident disease activity (NEDA) status in patients with relapsing-remitting multiple sclerosis (RRMS) from 7 multiple sclerosis outpatient clinics in Central Italy. METHODS: We analyzed data of patients with RRMS who started an oral agent, namely DMF or FNG, either as first treatment (naives) or after switching from self-injectable drugs (switchers). We performed a propensity score (PS)-based nearest-neighbor matching within a caliper of 0.05 to select patients with homogeneous baseline characteristics. Pairwise censoring was adopted to adjust for difference in length of follow-up between the 2 treatment groups. Comparisons were then conducted in matched samples with Cox models (stratified by center) with NEDA-3 as the main outcome. NEDA-3 was defined as no relapses, no disability worsening, and no MRI activity. RESULTS: Overall, 483 and 456 patients eligible for analysis started on FNG and DMF, respectively. The PS-matching procedure retained a total of 550 patients (275 per group). After a median on-study follow-up of 18 months, the proportions of patients with NEDA-3 were similar (FNG 73%, DMF 70%; hazard ratio [HR] 0.74, p = 0.078). Subgroup analyses showed a comparable effectiveness of the 2 drugs in naives (n = 170, HR 1.15, p = 0.689), whereas FNG was superior to DMF in the achievement of NEDA-3 status among switchers (n = 380, HR 0.57, p = 0.007). CONCLUSION: We found no significant difference between FNG and DMF on NEDA-3 status, while subgroup analyses suggest the superiority of FNG over DMF in patients switching from self-injectable drugs. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RRMS, DMF and FNG have comparable efficacy in treatment-naive patients and that FNG is superior to DMF in patients switching from self-injectable drugs.

The Prevalence of Multiple Sclerosis in the Metropolitan Area of Rome: A Capture-Recapture Analysis.

BACKGROUND: Limited data are available on the prevalence of multiple sclerosis (MS) in central Italy. The objective of this study is to estimate MS prevalence in the metropolitan area of Rome. METHODS: We used the capture-recapture method to calculate prevalence estimates in the study area. The selected prevalence day was December 31, 2015. A total of 1,007 patients, with a definite diagnosis of MS according to the revised McDonald's criteria, were considered for crude, age- and sex-specific prevalence estimation. RESULTS: The overall crude prevalence rate was 146.2 cases per 100,000 (95% CI 119.9-172.5). A higher prevalence rate was recorded in females (194.1, 95% CI 149.6-238.6) than in males (93.0, 95% CI 67.2-118.8) with a female to male ratio of 1.8. Age-specific prevalence peaked in the 25-34 , 35-44 and 45-54 years class; moreover, it was found to increase up to the 45-54 years age group in females and the 35-44 years age group in males, decreasing thereafter. CONCLUSION: The results confirm that the metropolitan area of Rome is a high-risk area for MS.

Prognostic indicators in pediatric clinically isolated syndrome.

OBJECTIVE: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. METHODS: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. RESULTS: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46-7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. INTERPRETATION: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729-739.

Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis.

In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis. As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively. In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference. Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.

Natalizumab Affects T-Cell Phenotype in Multiple Sclerosis: Implications for JCV Reactivation.

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects.

The Use of Immunosuppressant Therapy for Multiple Sclerosis in Italy: A Multicenter Retroprospective Study.

INTRODUCTION: Immunosuppressive agents (ISA) have been used in multiple sclerosis (MS) for decades, frequently as off label licensed therapies. Given the new MS treatment landscape, what place do ISA have in combating MS? METHODS: We conducted a retrospective multicentre study to investigate the frequency of ISA prescription in 17 Italian MS centres, and to describe the clinical factors related to ISA use. RESULTS: Out of 6,447 MS patients, 2,034 (31.6%) were treated with ISA, with Azathioprine being the most frequently used ISA overall. MS patients treated with ISA alone were more frequently affected by the progressive course (both primary and secondary) of the disease (RRR 5.82, 95% CI 4.14-8.16, p<0.0001), had higher EDSS (RRR 3.69, 95% CI 2.61-5.21, p<0.0001), higher assignment age (RRR 1.04, 95% CI 1.03-1.06, p<0.0001) than patients treated with only disease modifying drugs (DMDs). CONCLUSIONS: Progressive course, higher EDSS, higher assignment age were the strongest predictors of ISA prescription and use in our population.

A dual concurrent mechanism explains trigeminal neuralgia in patients with multiple sclerosis.

OBJECTIVE: In this clinical and neuroimaging study, we sought information on the possible role of neurovascular compression in multiple sclerosis (MS)-related trigeminal neuralgia (TN). METHODS: After screening 1,628 consecutive patients with MS, we enrolled 28 patients with definite unilateral MS-related TN. In these patients, we acquired dedicated 3T MRI scans, identified pontine demyelinating plaques, and, using highly specific diagnostic criteria, distinguished possible neurovascular compression. RESULTS: MRI scans in most patients showed a demyelinating plaque in the pontine trigeminal root entry zone on the affected side. The frequency of the neurovascular compression and its association with the pontine demyelinating plaque were higher on the affected than on the unaffected side (54% vs 0%; p = 0.0001). CONCLUSIONS: Our observation that in many patients with MS-related TN a pontine demyelinating plaque and neurovascular compression coexist should prompt neurologists to seek possible neurovascular compression in patients with MS-related TN.

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.