Stable Multiple Sclerosis Research Articles

Association of circulating anti-CD64 IgM levels with favourable long-term clinical outcomes in multiple sclerosis patients

Circulating levels of IgM anti-CD64, an immunosuppressive antibody recently identified in long-term stable multiple sclerosis (MS) patients, were found to fluctuate over time in MS patients. Antibody-positive patients showed a significantly lower annualized relapse rate value as well as reached sustained disability worsening and had a relapse in a significantly longer median time than those without antibody. Disease-modifying therapies (DMTs) only were the covariate influencing both the relapse occurrence and the disability accrual. Serum IgM anti-CD64 levels are associated with maintenance of clinical stability in MS and may be tested as a candidate biomarker predictive of benign course and favourable long-term response to DMTs treatment.

Oxidative Stress Related to Iron Metabolism in Relapsing Remitting Multiple Sclerosis Patients With Low Disability.

Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in “untreated” group and “treated” group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular “MS untreated” showed higher mean values (mean = 114.5, SD = 39.37 μg/dL) than CTRL (mean 78.6, SD = 27.55 μg/dL p = 0.001) and “MS treated” (mean = 72.4, SD = 38.08 μg/dL; p < 0.001). Moreover, “MS untreated” showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.

Tolerability, treatment satisfaction and quality of life outcomes in stable multiple sclerosis patients switched from injectable therapies to auto injected intramuscular interferon beta 1a: The SFERA study

BackgroundInterferon beta (IFNB) and Glatiramer acetate, long-term first line disease modifying treatments (DMTs) for multiple sclerosis (MS), have different injection frequencies crucial for injection site related side effects. We aimed at investigating whether switching to intramuscular IFNB-1a injected once/week with the Avonex®Pen™ device improves treatment tolerability and quality of life in stable MS patients. MethodsClinically stable MS patients, whom their treating neurologist switched from high frequency injectable DMTs to weekly intramuscular IFNB-1a because of bothersome injection site reactions, were included. Injection site and systemic tolerability were measured by a composite 100 mm visual analogue scale at screening, months 4 and 12. Treatment satisfaction, quality of life, relapses and EDSS progression were also recorded. The primary endpoint was change in injection site tolerability from screening to Month 4. Descriptive statistics and Wilcoxon paired signed-rank tests were applied. ResultsThe median injection site tolerability and systemic tolerability were significantly improved at months 4 (n = 36) and 12 (n = 33) [change −51.60 (IQR: −60.13, −39.60) mm (p < 0.0001); −26.00 (−54.00, 2.25) mm (p = 0.002)]. Median treatment satisfaction was significantly improved at month 12 [change of 18.00 (2.00, 47.50) mm (p = 0.0003)]. Physical and mental components of the SF-36 did not change significantly, and 30/33 (90.9%) and 33/33 (100%) patients were free from relapses and EDSS progression at month 12. ConclusionsWeekly intramuscular IFNB-1a may represent an alternative treatment option for clinically stable MS patients suffering from intolerable injection-related side effects under treatment with high frequency injectable DMTs.

Multiple sclerosis patients who are stable on interferon therapy show better outcomes when staying on same therapy than patients who switch to another interferon.

BackgroundReal-world outcomes from staying on an interferon beta (IFNβ) vs switching to another IFNβ could help guide treatment decisions. This study’s objective was to compare outcomes of stable multiple sclerosis (MS) patients on an IFNβ who stayed on therapy vs those who switched to another IFNβ.MethodsMS patients were identified from the Optum Insights Clinformatics Data Mart Multi-Plan who were 18–64 years old and relapse-free (stable) over 1 year while continuously being treated with an IFNβ. Patients were propensity score matched 3:1 using age, gender, initial IFNβ, adherence, and month and year for patients who stayed on the initial IFNβ (No Switch) to patients who switched to another IFNβ (Switch). Patients had to be continuously enrolled for 1 year prior to and 1 year after the index date (date of the first claim of the switched-to IFNβ or the match date when continuing on initial IFNβ treatment). Patients were enrolled with index dates between January 1, 2005 and September 30, 2014. Relapses were recorded during the 1-year follow-up period after index date.ResultsAfter matching, there were 381 patients in the Switch group and 1,143 in the No Switch group. Baseline characteristics were well matched between groups (average age 46 years, 72% female). The percentage of patients experiencing a relapse during the follow-up was significantly higher in the Switch group than in the No Switch group (21% vs 12%, P<0.0001). Annual relapse rate during the follow-up was significantly higher in the Switch group than in the No Switch group (0.35 vs 0.20, P<0.0001).ConclusionMS patients stable on IFNβ therapy who remain on initial therapy had significantly better outcomes (lower annual relapse rate and percentage of patients with relapses) than patients who switched to another IFNβ. This supports the benefits of allowing patients to remain on current IFNβ therapy when stable.

Higher Neural Correlates in Multiple Sclerosis Patients with Neurogenic Overactive Bladder Following Treatment with Intradetrusor Injection of OnabotulinumtoxinA

OnabotulinumtoxinA is a well described treatment of neurogenic overactive bladder. While motor effects on the detrusor muscle have been extensively studied, the sensory effects have not. The aim of this study was to evaluate the impact of intradetrusor onabotulinumtoxinA injection on brain activity in female patients with multiple sclerosis and neurogenic overactive bladder. We prospectively studied 12 women with stable multiple sclerosis and neurogenic overactive bladder using concurrent functional magnetic resonance imaging and urodynamic studies prior to and 6 to 10 weeks following onabotulinumtoxinA injection. Individual functional magnetic resonance imaging activation maps at the time of strong urgency were averaged before and after onabotulinumtoxinA injection where areas of significant activation were identified. After onabotulinumtoxinA injection functional magnetic resonance imaging activation increased in the right cingulate body (p = 0.0012), the left posterior cingulate (p = 0.02), the left anterior cingulate (p = 0.0015), the right prefrontal cortex (p = 0.0015), the insula (p = 0.0138) and the pons micturition center (p = 0.05). Sparse areas showed decreased activity, including the left cerebellum (p = 0.001), the left fusiform gyrus (p = 0.065) and the bilateral lentiform nucleus (p = 0.026). Intradetrusor injection of onabotulinumtoxinA appeared to increase the activity of most brain regions known to be involved in the sensation and process of urinary urgency in female patients with multiple sclerosis and neurogenic overactive bladder. To our knowledge this is the first study of its kind to evaluate the possible effects of onabotulinumtoxinA at the human brain level where sensory awareness is located. This activation pattern may be used to further phenotype patients to optimize therapy or determine the sensory effects of onabotulinumtoxinA beyond the bladder.

Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis

We have previously shown that SIRT1 mRNA expression was significantly lower in relapsing MS patients compared to those in remission. Our goal was to longitudinally investigate the role of active, phosphorylated SIRT1 (p-SIRT1) as a potential biomarker of relapse and predictor for response to glatiramer acetate (GA) treatment in patients with relapsing remitting multiple sclerosis (MS). We also want to investigate the downstream effects of SIRT1 activation by measuring the trimethylation of histone 3 at lysine 9 (H3K9me3). A cohort of 15 GA-treated patients was clinically monitored using the Expanded Disability Status Scale (EDSS) and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12 months after initiation of the therapy. P-SIRT1 and H3K9me3 levels were assayed by Western blotting using specific antibodies. Statistically significant lower levels of p-SIRT1 protein (p < 0.0001) and H3K9me3 (p = 0.001) were found during relapses when compared to stable MS patients. Non-responders to GA treatment were defined as patients who exhibited at least two relapses following initiation of GA treatment. Statistically significant lower levels of p-SIRT1 protein (p = 0.02) and H3K9me3 (p = 0.004) were found in GA non-responders compared to responders. Using receiver operating characteristic analysis, area under the curve (AUC) for p-SIRT1 was 77% (p = 0.007) and for H3K9me3 was 81% (p = 0.002) for prediction of relapse. For predicting responsiveness to GA treatment, AUC was 75% (P = 0.01) for H3K9me3. Our data suggest that p-SIRT1 and H3K9me3 could serve as potential biomarkers for MS relapse. In addition, H3K9me3 could serve as possible biomarker to predict response to GA treatment.

Monosodium Urate Crystals Activate the Inflammasome in Primary Progressive Multiple Sclerosis.

Inflammasome-driven inflammation is postulated to play a role in multiple sclerosis (MS), but there is no direct evidence that the nod-like receptor protein 3 (NLRP3) inflammasome is involved in MS pathogenesis. Uric acid was shown to be one of the “danger” signals involved in the activation of NLRP3 inflammasome; notably, the concentration of uric acid is increased in the serum and in the cerebrospinal fluid of MS individuals. To better investigate the role of the NLRP3 inflammasome in MS-associated inflammation, we primed with lipopolysaccharide and stimulated with monosodium urate crystals PBMCs of 41 MS patients with different disease phenotypes. Eleven individuals with primary progressive MS (PPMS), 10 individuals with stable relapsing–remitting MS (SMS), 10 individuals with acute relapsing–remitting MS (AMS), 10 individuals with benign MS were analyzed; 10 healthy controls were enrolled as well in the study. The expression of the NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1, caspase-8, IL-1β, and IL-18 inflammasome genes was evaluated by RT-PCR. NLRP3 and ASC-speck protein expression was analyzed by FlowSight AMNIS, whereas production of the pro-inflammatory cytokines IL-1β and IL-18 and of caspase-1 and caspase-8 was measured by ELISA in supernatants. Results showed that uric acid serum concentration was significantly increased in PPMS; in these and in AMS patients, mRNA for NLRP3, ASC, and IL-18 was upregulated as well, but caspase-8 mRNA was upregulated only in PPMS. Expression of NLRP3 and ASC-speck protein was significantly increased in PPMS, SMS, and AMS patients, but IL-18 and caspase-8 production was significantly increased only in PPMS, in whom a direct correlation between hyperuricemia and caspase-8 was detected. The NLRP3/caspase-8 inflammasome pathway is activated in PPMS, possibly as a consequence of hyperuricemia. Therapeutic strategies reducing NLRP3 activation and/or lowering hyperuricemia could be useful in the therapy of PPMS.

A 37 Year Old Female Dance Instructor with Leg and Buttock Pain

HISTORY: A 37 year old female dance instructor with a history of stable multiple sclerosis presented with a 5 year history of left buttock and posterolateral thigh pain with radiation to the plantar surface of her foot that began during pregnancy. Pain was minimal at rest and aggravated by prolonged sitting and activities such as dancing, bicycling, and hiking. Pain progressed and now markedly limited activity. She reported tingling of the posterolateral calf and plantar surface of the foot. She denied weakness. Chiropractic care provided no relief. Previously obtained lumbar spine MRI was unremarkable and the patient completed 6 months of physical therapy without improvement. PHYSICAL EXAMINATION: There was no appreciable deformity, malalignment, or rotation of the lumbar spine, hips, or knees. She walked with a non-antalgic gait, including normal heel and toe walking. Palpation of deep left gluteal muscles reproduced pain with radiation down the left lower limb. Range of motion of the lumbar spine and hips was grossly normal. Manual muscle testing of the lower limbs was normal. Passive hip flexion, abduction, and external rotation, as well as flexion, adduction, and internal rotation of the left hip reproduced pain. Remainder of provocative lumbar spine and hip maneuvers, including straight leg raise, were normal. She was neurovascularly intact. DIFFERENTIAL DIAGNOSIS: Chronic Piriformis Strain Lumbosacral Radiculopathy Hip Osteoarthritis Multiple Sclerosis Flare Sciatic, Tibial, or Peroneal Neuropathy TEST AND RESULTS:FigureMRI Lumbosacral Plexus: 2.8 X 2.5 X 3.0 cm mass along the left sciatic nerve between the gluteus maximus and quadratus femoris with extension into the ischiofemoral space, consistent with cystic schwannoma FINAL WORKING DIAGNOSIS: Left sciatic nerve tumor, concern for cystic schwannoma TREATMENT AND OUTCOMES: Neurosurgery evaluation Underwent surgical resection of mass 16 weeks after surgery, reported 100% resolution of her symptoms

PD04-01 CHANGES IN BRAIN ACTIVITY FOLLOWING INTRADETRUSOR INJECTION OF ONABOTULINUMTOXINA IN PATIENTS WITH MULTIPLE SCLEROSIS: AN FMRI STUDY

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction I1 Apr 2018PD04-01 CHANGES IN BRAIN ACTIVITY FOLLOWING INTRADETRUSOR INJECTION OF ONABOTULINUMTOXINA IN PATIENTS WITH MULTIPLE SCLEROSIS: AN FMRI STUDY Rose Khavari, Christof Karmonik, Saba Elias, and Timothy Boone Rose KhavariRose Khavari More articles by this author , Christof KarmonikChristof Karmonik More articles by this author , Saba EliasSaba Elias More articles by this author , and Timothy BooneTimothy Boone More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.279AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES OnabotulinumtoxinA (BTX-A) is a well-described treatment for Neurogenic Detrusor Overactivity (NDO) and while its motor effects on detrusor muscle is extensively studied, its sensory effects are not. Prior functional neuroimaging studies have suggested that women with overactive bladder have increased brain activity in the cingulate cortex, insula, and frontal cortex in response to bladder filling. The aim of this study was to evaluate the impact of intradetrusor BTX-A on brain activity in female multiple sclerosis (MS) patients with NDO using concurrent functional magnetic resonance imaging (fMRI) and UDS in a priori regions of interest. METHODS We conducted a prospective study of 12 women with stable MS and NDO undergoing fMRI with simultaneous UDS prior to and 6-weeks following BTX-A. During the filling phase patients signalled the strong urgency. From individual fMRI activation maps at strong urgency average fMRI activation map in MNI (Montreal Neuroimaging Institute) space were created for pre and post BTX-A from which areas of significant activation were identified (p<0.05). RESULTS fMRI activation increased post BTX-A in the right cingulate body (x (right positive),y (posterior positive),z (inferior positive) coordinates = 17,4,39, p=0.0012), ), the left posterior cingulate (-7,-37,22,p=0.02), the left anterior cingulate (-3,24,8,p=0.0015), the right prefrontal cortex (3,51,46,p=0.0015), the insula (32,12,14,p=0.0138) and the pons micturition center (3,-29,-28,p=0.05). Areas that showed decreased activity were sparse and included the left cerebellum (-31,-63,-62,p=0.001), the left fusiform gyrus (-40,-3,-28,p=0.065) and the bilateral lentiform nucleus (-17,6,-9 and 18,2,-9, p=0.026). CONCLUSIONS Intradetrusor injection of BTX-A appears to increase the activity of the brain regions known to be involved in sensation and process of urinary urgency in female MS patients with NDO. This is the first study of its kind to evaluate the possible sensory effects of BTX-A at the human brain level where sensory awareness is located. This pattern of activation may be used to phenotype patients further to optimize therapy or to uncover sensory effects of onabotulinumtoxinA beyond the bladder. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e77 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Rose Khavari More articles by this author Christof Karmonik More articles by this author Saba Elias More articles by this author Timothy Boone More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Immune-related miRNA expression patterns in peripheral blood mononuclear cells differ in multiple sclerosis relapse and remission

MiRNAs were shown to participate in development of autoimmune inflammatory process in multiple sclerosis (MS). To investigate miRNAs involvement in relapse-remission MS course, we analyzed expression of immune-related miRNAs in PBMC of treatment-naïve relapsing and remitting MS patients and healthy controls. The upregulation of miR-126-3p, miR-146b-5p, miR-155, miR-196a-5p, miR-21-5p, miR-223-3p, miR-326 and miR-379-5p in remission compared to relapse was observed; when apply gender stratification, miR-223-3p and miR-379-5p were upregulated only in men. Therefore, miRNAs play essential role in maintaining stable MS course and this process has certain gender-specific differences.

A Pilot Investigation of Natural Killer Cell Function and Phenotypes in Stable and Active Multiple Sclerosis Patients

Background: Previous studies have reported impaired cytotoxic activity in Natural Killer (NK) CD56Dim and CD56Bright cell phenotypes in peripheral blood associated with Multiple Sclerosis (MS). Recently it has been suggested that NK cell phenotype could be associated with new lesions on Magnetic resonance imaging (MRI) and may be used as an immunological indicator of disease activity. This project, for the first time, investigates NK cell cytotoxicity in MS patients with active and stable lesions.Methods: NK cell cytotoxic activity and NK CD56Dim and CD56Bright cell phenotypes were examined in MS patients using flow cytometry. Isolated NK cells were labelled with antibodies to determine CD56Dim and CD56Bright NK cells and cytotoxic function using target cells (K562). Seven patients (aged 38.0 ± 3.21) with stable Relapsing Remitting MS (RRMS) who had previously received alemtuzumab (Lemtrada®), five patients with active MS (aged 32.66 ± 5.17) on nil medication and five healthy controls (aged 34.4 ± 6.12) participated.Results: There were no significant differences for NK cell cytotoxic activity and NK CD56Dim and CD56Bright phenotypes between stable RRMS, active RRMS and healthy controls.Conclusion: Clear associations between NK cell cytotoxicity and clinical MS subtypes in this study were not identified.

Neuroinflammation following disease modifying therapy in multiple sclerosis: A pilot positron emission tomography study

IntroductionChronic activation of microglia accelerates the neurodegenerative process in multiple sclerosis (MS). Although disease modifying therapy (DMT) is reportedly effective for neuroinflammatory responses in MS, the progression of neuroinflammation after DMT remains unclear. MethodsWe evaluated microglial activation in six clinically stable relapsing-remitting MS patients after DMT by quantifying changes in translocator protein (TSPO) density using PET with [11C]DPA713, a selective TSPO tracer for microglial activation. All patients underwent [11C]DPA713 PET scans twice, and the scans were conducted one year apart. The binding potential (BPND) of the tracer was estimated using a simplified reference tissue model. Results[11C]DPA713 BPND measured at 6months after DMT was significantly higher in the MS group than that in the control group. Compared with the first PET measurement, the one-year PET measurement revealed significantly elevated [11C]DPA713 BPND in broader brain regions covering the temporal and parietal cortices after one year of DMT. ConclusionsThe current results indicate that microglial activation may proceed in the entire brain of clinically stable MS patients even after receiving DMT.

A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis.

ObjectiveThe objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).MethodsSeventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months.ResultsrHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of Cmax and AUC0–Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort.ConclusionsSingle doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis.

Multiple sclerosis (MS) is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R) is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further investigated its phenotypic expression in MS and experimental autoimmune encephalomyelitis conditions. By quantitative reverse transcription polymerase chain reaction and flow cytometry, we analyzed the P2X7R expression in human mononuclear cells of peripheral blood from stable and acute relapsing-remitting MS phases. Human monocytes were also challenged in vitro with pro-inflammatory stimuli such as the lipopolysaccharide, or the P2X7R preferential agonist 2′(3′)-O-(4 Benzoylbenzoyl)adenosine 5′-triphosphate, before evaluating P2X7R protein expression. Finally, by immunohistochemistry and immunofluorescence confocal analysis, we investigated the P2X7R expression in frontal cortex from secondary progressive MS cases. We demonstrated that P2X7R is present and inhibited on peripheral monocytes isolated from MS donors during the acute phase of the disease, moreover it is down-regulated in human monocytes after pro-inflammatory stimulation in vitro. P2X7R is instead up-regulated on astrocytes in the parenchyma of frontal cortex from secondary progressive MS patients, concomitantly with monocyte chemoattractant protein-1 chemokine, while totally absent from microglia/macrophages or oligodendrocytes, despite the occurrence of inflammatory conditions. Our results suggest that inhibition of P2X7R on monocytes and up-regulation in astrocytes might contribute to sustain inflammatory mechanisms in MS. By acquiring further knowledge about P2X7R dynamics and identifying P2X7R as a potential marker for the disease, we expect to gain insights into the molecular pathways of MS.

Programmed death 1 is highly expressed on CD8+ CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus.

Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8+ T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8+ CD57+ T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8+ CD57+ T cells with high expression of PD-1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8+ CD57+ T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

IL-22, GM-CSF and IL-17 in peripheral CD4+ T cell subpopulations during multiple sclerosis relapses and remission. Impact of corticosteroid therapy.

Multiple sclerosis (MS) is thought to be a Th17-mediated dysimmune disease of the central nervous system. However, recent publications have questioned the pathogenicity of IL-17 per se and rather suggest the implication of other Th17-related inflammatory mediators. Therefore, we studied the expression of GM-CSF, IL-22, IL-24, IL-26 and CD39 in peripheral blood mononuclear cells (PBMCs) from MS patients during relapses, remission and following corticosteroid treatment. We performed qPCR to measure mRNA levels from ex vivo or in vitro-stimulated PBMCs. Cytokine levels were determined by ELISA. We used flow cytometry to assess GM-CSF+, IL-22+ and CD39+ cells in relationship to IL-17+ CD4+ T cells. Our results showed that IL-22 mRNA and IL-22+CD4+ lymphocytes are increased in circulating cells of relapsing MS patients compared to remitting patients while GM-CSF was unchanged. We have further shown that 12.9, 39 and 12.4% of Th17 cells from MS patients during relapses expressed IL-22, GM-CSF and CD39 respectively. No changes in these proportions were found in stable MS patients. However, the majority of GM-CSF+ or IL-22+ T cells did not co-express IL-17. GM-CSF mRNA, but not IL-22 mRNA, was dramatically decreased ex vivo by ivMP. Our results contribute to a better characterisation of Th17, Th22 and ThGM-CSF cells in the setting of MS and according to disease activity.

SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis

SIRT1, a NAD dependent histone and protein deacetylase, is a member of the histone deacetylase class III family. We previously showed that SIRT1 mRNA expression is significantly lower in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients during relapses than in stable patients. We have now investigated SIRT1 as a possible biomarker to predict relapse as well as responsiveness to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2years, a cohort of 15 GA-treated RRMS patients were clinically monitored using the Expanded Disability Status Scale and assessed for MS relapses. Blood samples collected from MS patients were analyzed for levels of SIRT1 and histone H3 lysine 9 (H3K9) acetylation and dimethylation. During relapses, MS patients had a lower expression of SIRT1 mRNA than did stable MS patients. In addition, there was a significant decrease in H3K9 dimethylation (H3K9me2) during relapses in MS patients when compared to stable patients (p=0.01). Responders to GA treatment had significantly higher SIRT1 mRNA (p=0.01) and H3K9me2 levels than did non-responders (p=0.018). Receiver operating characteristic analysis was used to assess the predictive power of SIRT1 and H3K9me2 as putative biomarkers: for SIRT1 mRNA, the predictive value for responsiveness to GA treatment was 70% (p=0.04) and for H3K9me2 was 71% (p=0.03). Our data suggest that SIRT1 and H3K9me2 could serve as potential biomarkers for evaluating patients' responsiveness to GA therapy in order to help guide treatment decisions in MS.

PND13 - Stable Multiple Sclerosis Patients on an Interferon Therapy Have Better Outcomes When Staying on Therapy than Patients who Switch to Another Interferon

PND13 - Stable Multiple Sclerosis Patients on an Interferon Therapy Have Better Outcomes When Staying on Therapy than Patients who Switch to Another Interferon

Relevance of antiphospholipid antibodies in multiple sclerosis: A systematic review and meta analysis.

The relationship between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) is unclear. To evaluate a link between aPL and MS. EMBASE and PubMed search to August 2016; Peto's odds ratio (OR) meta-analysis. The pooled prevalence of participants positive for IgG and IgM anticardiolipin (aCL) from 12 case-control studies was superior in MS than controls (6.8% vs 1.8%, p = 0.01 and 8.58% vs 2.18%, p = 0.001) with medium and high heterogeneities respectively (I2 = 48.55% and 68.13%). The pooled prevalence of participants positive for IgG anti-beta2glycoprotein-I (aβ2GPI) from seven case-control studies was lower in MS than controls (0.93% vs 4.02%) with high heterogeneity (I2 = 53.92%) though the pooled prevalence of participants positive for IgM aβ2GPI was similar (7.24% vs 6.13%) with high heterogeneity (I2 = 52.85%). Five cohorts compared IgG/IgM aCL and IgM aβ2GPI in stable/remission vs active/relapsing MS: the pooled prevalence of IgG aCL was similar in active/relapsing and stable/remission MS (19% vs 18.9%) but the pooled prevalence of IgM aCL was higher in active than in stable MS (36.9% vs 21%, p < 0.0001) as well as that of IgM β2GPI (40.5% vs 3.2%, p < 0.0001) with no heterogeneity. Data from case-control studies do not support a link between IgG/IgM aPL and MS. Data from cohort studies comparing active vs stable MS indicate a strong link between aPL of IgM isotype and active/relapsing MS but in the absence of aPL titres to comment upon this may either represent an epiphenomenon of active neuro-inflammation or natural autoantibodies devoid of pathogenic potential. Data expressed as frequency of aPL positive participants rather than average titres preclude further assumptions.

The association between retinal nerve fibre layer thickness and N-acetyl aspartate levels in multiple sclerosis brain normal-appearing white matter: a longitudinal study using magnetic resonance spectroscopy and optical coherence tomography.

N-acetyl aspartate (NAA) assessed using proton magnetic resonance spectroscopy (1 H MRS) has a high pathological specificity for axonal density. Retinal nerve fibre layer thickness (RNFLT) measured by using optical coherence tomography is increasingly used as a surrogate marker of neurodegeneration in multiple sclerosis (MS). Our aim was to investigate the relation between RNFLT and NAA/creatine in brain normal-appearing white matter (NAWM), their dynamics over time and the association with clinical outcome measures in relapsing MS. T2 WM lesions served as control tissue. Forty-three MS patients underwent standardized neurological examination including the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC) score, optical coherence tomography and magnetic resonance imaging including 1 H MRS at baseline and after 1 year. At baseline, NAA/creatine level was lower in T2 WM lesions than in NAWM (1.64 ± 0.16 vs. 1.88 ± 0.24, P < 0.001). Lowest levels were found in secondary progressive MS (SPMS). Mean RNFLT was higher in clinically isolated syndrome than in the combined group of relapsing-remitting MS and SPMS (99.8 ± 12.3 μm vs. 92.4 ± 12.8 μm, P = 0.038). In all patients, mean RNFLT decreased by 1.4% during follow-up. At baseline, MSFC z-scores correlated with NAA/creatine levels both in NAWM (r = 0.42; P = 0.008) and T2 WM lesions (r = 0.52, P = 0.004). NAWM NAA/creatine variation correlated with the RNFLT change over 1 year (ρ = 0.43, P = 0.046). N-acetyl aspartate/creatine level reduction correlated with RNFLT thinning over 1 year in an EDSS stable MS cohort suggesting that these techniques might be sensitive to detect subclinical disease progression.