Relapsing Multiple Sclerosis Patients Research Articles

CSF CXCL13 and Chitinase 3-like-1 Levels Predict Disease Course in Relapsing Multiple Sclerosis

Several biomarkers from multiple sclerosis (MS) patients’ biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.

T Lymphocyte Serotonin 5-HT7 Receptor Is Dysregulated in Natalizumab-Treated Multiple Sclerosis Patients.

Serotonin (5-HT) is known as a potent immune cell modulator in autoimmune diseases and should be protective in the pathogenesis of multiple sclerosis (MS). Nevertheless, there is limited knowledge about receptors involved in 5-HT effects as well as induced mechanisms. Among 5-HT receptors, the 5-HT7 receptor is able to activate naïve T cells and influence the inflammatory response; however, its involvement in the disease has never been studied so far. In this study, we collected blood sample from three groups: acute relapsing MS patients (ARMS), natalizumab-treated MS patients (NTZ), and control subjects. We investigated the 5-HT7 expression on circulating lymphocytes and evaluated the effects of its activation on cytokine production with peripheral blood mononuclear cell (PBMC) cultures. We found a significant increase in the 5-HT7 surface expression on T lymphocytes and on the different CD4+ T cell subsets exclusively in NTZ-treated patients. We also showed that the selective agonist 5-carboxamidotryptamine (5-CT)-induced 5-HT7R activation significantly promotes the production of IL-10, a potent immunosuppressive cytokine in PBMCs. This study provides for the first time a dysregulation of 5-HT7 expression in NTZ-MS patients and its ability to promote IL-10 release, suggesting its protective role. These findings strengthen the evidence that 5-HT7 may play a role in the immuno-protective mechanisms of NTZ in MS disease and could be considered as an interesting therapeutic target in MS.

High leukocyte-to-lymphocyte ratio is associated with acute relapse in multiple sclerosis patients

ABSTRACT Background Multiple sclerosis (MS) is an immune-mediated chronic disease characterized by inflammatory demyelination in the central nervous system (CNS). As there is limited evidence on whether leukocyte-to-lymphocyte ratios (LLRs) are associated with MS, we carried out an investigation on the association between LLRs and MS as favorable markers and aimed to determine the cut-off LLR for the identification of early-stage MS patients. Methods A matched case-control study enrolled a total of 120 MS inpatients and 120 age- and sex-matched non-MS inpatients from January 2013 to June 2018. LLRs were tested from peripheral venous blood routinely during hospitalization. Conditional logistic regression analyses were used to explore differences in LLRs between cases and controls. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic ability of LLRs and determine the best cut-off value. Disease disability was assessed using the Expanded Disability Status Scale (EDSS). Results The LLR was significantly associated with MS in hospitalized patients (OR: 2.372, 95% CI: 1.282 to 4.387, p < 0.001) after adjusting for potential confounders. The area under the curve (AUC) value was 0.793 (95% CI: 0.736 to 0.851). The cut-off value for LLR was 3.18, with sensitivity and specificity values of 62.5% (95% CI: 53.2% to 71.2%) and 88.3% (95% CI: 81.2% to 93.5%), respectively. The EDSS scores of the higher LLR group were significantly higher than the lower group. Conclusion Systemic inflammation measured using LLRs may be an inflammatory marker among MS inpatients. LLRs may serve as favorable inflammatory markers with which to discriminate MS among Chinese subjects.

Acute infusion effects in relapsing multiple sclerosis patients receiving alemtuzumab under a modified prophylaxis regimen

BackgroundUse of alemtuzumab in relapsing multiple sclerosis (RMS) is limited by safety concerns, notably risk of rare, serious vascular events. Along with other vital sign (VS) changes, acute increase in systolic blood pressure (SBP) is monitored as a marker of vascular risk. Peri-infusion prophylaxis is used to manage clinical risk by moderating cytokine release; protocols are not fully specified and vary across sites. Here, we report a modified prophylaxis regimen developed at Maritime Neurology. This single-center observational cohort study (NCT04633967) aimed to examine acute responses (VS events and infusion-associated reactions) in RMS patients receiving alemtuzumab infusion under this regimen. In a post hoc analysis, we examined incidence of acute SBP increase at this clinic versus the Bayshore network of Canadian infusion centers, where a standard prophylaxis regimen is used. MethodsAlemtuzumab was infused on 5 consecutive days (Course 1; n = 29) and 3 consecutive days one year later (Course 2; n = 28). In addition to intravenous methylprednisolone 500mg on each infusion day, patients received daily prophylactic treatment with oral prednisone 50mg from 5 days before to 5 days after treatment (infusion days excepted) and oral H1 and H2 antihistaminics from 7 days before to 7 days after treatment. Excursions in SBP and other VS were relative to prespecified ranges; persistent excursions were those for which two sequential measurements were outside these ranges. In comparing VS events at Maritime Neurology and the Bayshore centers, acute SBP increase was defined as ≥20 mmHg increase in mean SBP, or any SBP reading ≥20% over patient's pre-course baseline. ResultsMean (SD) VS were within range at pre-course and all other daily baselines. VS changes, including persistent excursions, were generally subclinical; all infusion-associated reactions were mild. One patient discontinued treatment after Course 1 due to immune thrombocytopenia purpura. Acute SBP increase occurred in 11/28 (39%) Maritime Neurology versus 367/610 (60%) Bayshore (p = 0.028). ConclusionThe modified peri-infusion prophylaxis regimen was well tolerated and may reduce incidence of acute SBP increase. FundingThis project was funded by Sanofi, Canada.

Immunological consequences of cladribine treatment in multiple sclerosis: A real-world study

BackgroundCladribine is a synthetic deoxyadenosine analogue approved for the treatment of highly active relapsing multiple sclerosis (RMS). Cladribine is considered to be a semi-selective immune-reconstitution therapy (IRT) that induces long-term remission following short course of treatment. Here, we evaluated the effect of cladribine on immune cell reduction and reconstitution during the first two years of treatment. MethodsWe analyzed our longitudinal, prospective, real-world cohort of 80 cladribine-treated RMS patients from two tertiary centers in Germany. Laboratory testing was conducted monthly and included evaluation of cellular as well as soluble parameters. Laboratory outcomes were correlated with infectious adverse events (AEs) and clinical or paraclinical disease activity. ResultsSelective alterations in immune cell populations occurred following cladribine treatment, with the most marked effects observed in year two of treatment. Specifically, a rapid reduction in CD56+ natural killer cells (nadir: month 1 (year 1) and 14 (year 2); -37 and -41% from baseline) was followed by a greater reduction in CD19+ B cells (nadir: month 2 and 14; -81 and -82%); a moderate effect on CD4+ (nadir: month 3 and 15; -48 and -61%) and CD8+ T cells (nadir: month 5 and 18; -40 and -48%). Despite the marked effect on B cells, immunoglobulin levels were unaffected. There was no or minimal effect on thrombocytes and innate immune cells. Clinical and paraclinical disease activity was unrelated to the observed immune alterations. Lymphopenia was the most commonly observed AE (86.3% of patients; grade III-IV lymphopenia: 38.8%). The cumulative incidence of infections was 55% with cladribine treatment, which were mostly mild or moderate. In total, 19 herpes infections developed in 8 (10%) cladribine-treated patients; all cases were dermatomal and 94.7% of the herpetic infections occurred during a period of lymphopenia. ConclusionsThe immunophenotyping data obtained in our real-world setting are comparable to those demonstrated in pivotal clinical trials and provide further evidence that cladribine may represent a form of IRT. However, regarding the side-effect profile of cladribine, severe lymphopenia (exceeding grade II CTCAE) was more frequent, which may have prompted the development of herpes infections. Of note, lymphocyte dynamics did not correlate with clinical and paraclinical measures of disease activity in the two-year follow-up period.

Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized Relapse Rate

BackgroundMultiple sclerosis (MS) is an inflammatory autoimmune disorder and the most common cause of non-traumatic disability in young adults. The Phase 3 OPTIMUM study evaluated the efficacy and safety of oral ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 modulator, vs. teriflunomide in patients with relapsing multiple sclerosis (RMS). The aim of this analysis was to assess the effect of ponesimod and other disease modifying treatments (DMTs) compared to placebo, as measured by 12-week confirmed disability accumulation (CDA) and annualized relapse rate (ARR) in RMS patients. MethodsA database was developed by Certara Inc. (USA) based on relevant clinical trials identified from searching the following sources: PubMed, clinicaltrials.gov, FDA and EMEA documents, and conference abstracts. This database consisted of 203 unique randomized controlled trials (RCTs) with 74 MS treatments and was subsequently filtered to include RCTs with more than 25 patients receiving monotherapy to treat RMS for at least 48 weeks. A model-based meta-analysis (MBMA) was performed on the filtered database to assess treatment effects measured by CDA and ARR. Analyzed data for CDA were digitized from published Kaplan-Meier plots. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time (proportional hazards). HRs were estimated for 12-week CDA for 17 DMTs vs. placebo. Additionally, mean ARR for each treatment arm was modelled, where relative effect versus placebo was estimated as a fixed effect parameter for each unique drug. A dose-response relationship was included if data for multiple doses were available. Relative treatment effect covariates explored for CDA and ARR included: percent of patients with relapsing-remitting MS (RRMS), trial start year, mean duration of disease, percent of patients who received DMTs within the prior 2 years (pDMT), mean number of relapses in the prior year, mean age, mean baseline EDSS score, and mean treatment duration (for ARR). ResultsThe 12-week CDA model utilized longitudinal data from 26 RCTs (18 unique treatments [including placebo]), 69 treatment arms, 31,160 patients). The ARR model utilized data from 40 RCTs (18 unique treatments [including placebo], 100 treatment arms, 33,686 patients). Compared to placebo, ponesimod significantly reduced 12-week CDA by 39% (HR: 0.61; 95% CI: 0.45–0.82) and reduced ARR by 53% (rate ratio [RR]: 0.47; 95% CI: 0.39–0.58). Except for three DMTs (interferon β-1b, glatiramer acetate, ozanimod), HR of 12-week CDA vs. placebo was significantly lower for the DMTs included in this analysis (HR range: 0.41 to 0.79). The ARR was significantly reduced for all DMTs compared to placebo (RR range: 0.29 to 0.82). A dose-response relationship indicated a potential dose-dependent effect (12-week CDA: 6 treatments; ARR: 8 treatments). Relative treatment effect was found to be significantly smaller in trials including more patients with prior DMT usage. Cross-trial heterogeneity in relative effects was assessed and found to be negligible; however, there is a possibility that confounders remain which may impact estimated relative treatment effects. ConclusionsCompared to placebo, ponesimod 20 mg significantly reduced both the risk of 12-week CDA and mean ARR, suggesting it has robust efficacy in the treatment of RMS.The study was funded by Janssen Research & Development, LLC.

Copy number variations across the blood–brain barrier in multiple sclerosis

ObjectiveMultiple sclerosis (MS) is a neuroinflammatory disease where immune cells cross the blood–brain barrier (BBB) into the central nervous system (CNS). What predisposes these immune cells to cross the BBB is still unknown. Here, we examine the possibility that genomic rearrangements could predisposespecific immune cells in the peripheral blood to cross the BBB and form sub‐populations of cells involved in the inflammatory process in the CNS.MethodsWe compared copy number variations in paired peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells from MS patients. Thereafter, using next generation sequencing, we studied the T‐cell receptor beta (TRB) locus rearrangements and profiled the αβ T cell repertoire in peripheral CD4+ and CD8+ T cells and in the CSF.ResultsWe identified deletions in the T‐cell receptor alpha/delta (TRA/D), gamma (TRG), and TRB loci in CSF cells compared to PBMCs. Further characterization revealed diversity of the TRB locus which was used to describe the character and clonal expansion of T cells in the CNS. T‐cell repertoire profiling from either side of the BBB concluded that the most frequent clones in the CSF samples are unique to an individual. Furthermore, we observed a difference in the proportion of expanded T‐cell clones when comparing samples from MS patients in relapse and remission with opposite trends in CSF and peripheral blood.InterpretationThis study provides a characterization of the T cells in the CSF and might indicate a role of expanded clones in MS pathogenicity.

How to choose initial treatment in multiple sclerosis patients: a case-based approach.

Immunotherapy dramatically changed the natural history of multiple sclerosis (MS), which was classically associated with severe disability. Treatment strategies advocate that early control of disease activity is crucial to avoid progressive disability, and the use of high efficacy drugs may be beneficial, but safety is a concern. Choosing the disease-modifying therapy is challenging in clinical practice and should be further discussed. To discuss the state of art of selecting the initial therapy for relapsing MS patients. We used a case-based approach followed by clinical discussion, exploring therapeutic options in different MS settings. We presented clinical cases profile compatible with the use of MS therapies, classified into moderate and high efficacy. In the moderate efficacy group, we discussed interferons, glatiramer acetate, teriflunomide and dimethyl fumarate, while in the high efficacy group we discussed fingolimod, cladribine, natalizumab, ocrelizumab, alemtuzumab and ofatumumab. Advances in MS treatment are remarkable. Strong evidence supports the use of early high efficacy therapy. However, biomarkers, clinical and radiologic prognostic factors, as well as patients' individual issues, should be valued and considered for a personalized treatment decision.

Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials.

ObjectiveThis study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).BackgroundPrevious post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.Design/MethodsIn this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup.ResultsHigh versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, −0.32% vs. −0.24%, p=0.044, and teriflunomide, −0.43% vs. −0.29%, p=0.002), thalamic volume (−0.56% vs. −0.31%, p=0.047 and −0.94% vs. −0.49%, p<0.001), and WM volume (−0.30% vs. −0.19%, p=0.083 and −0.38% vs. −0.18%, p=0.003) but not of cGM volume (−0.39% vs. −0.32%, p=0.337 and −0.49% vs. −0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients.ConclusionThis study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients.

COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab.

IntroductionThe SARS-CoV-2 pandemic necessitated better understanding of the impact of disease-modifying therapies on COVID-19 outcomes and vaccination. We report characteristics of COVID-19 cases and vaccination status in ofatumumab-treated relapsing multiple sclerosis (RMS) patients.MethodsCOVID-19 data analyzed were from the ongoing, open-label, long-term extension phase 3b ALITHIOS study from December 2019 (pandemic start) and post-marketing cases from August 2020 (ofatumumab first approval) up to 25 September 2021. COVID-19 cases, severity, seriousness, outcomes, vaccination status, and breakthrough infection were evaluated.ResultsAs of 25 September 2021, 245 of 1703 patients (14.4%) enrolled in ALITHIOS receiving ofatumumab (median exposure: 2.45 years) reported COVID-19 (confirmed: 210; suspected: 35). Most COVID-19 was of mild (44.1%) or moderate (46.5%) severity, but 9% had severe/life-threatening COVID-19. There were 24 serious cases (9.8%) with 23 patients hospitalized; 22 recovered and 2 died. At study cut-off, 241 patients (98.4%) had recovered or were recovering or had recovered with sequelae and 2 (0.8%) had not recovered. Ofatumumab was temporarily interrupted in 39 (15.9%) patients. Before COVID-19 onset, IgG levels were within the normal range in all COVID-19–affected patients, while IgM was < 0.4 g/l in 23 (9.4%) patients. No patient had a reinfection. Overall, 559 patients were vaccinated (full, 476; partial, 74; unspecified, 9). Breakthrough infection was reported in 1.5% (7/476) patients, and 11 reported COVID-19 after partial vaccination. As of 25 September 2021, the Novartis Safety Database (~ 4713 patient-treatment years) recorded 90 confirmed COVID-19 cases receiving ofatumumab. Most cases were non-serious (n = 80), and ten were serious (1 medically significant, 9 hospitalized, 0 deaths). Among 36 of 90 cases with outcomes reported, 30 recovered and 6 did not recover.ConclusionCOVID-19 in RMS patients on ofatumumab was primarily of mild/moderate severity and non-serious in these observational data. Most recovered from COVID-19 without treatment interruption. Two people died with COVID-19. Breakthrough COVID-19 despite being fully/partially vaccinated was uncommon.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-022-00341-z.

Olfactory threshold predicts treatment response in relapsing multiple sclerosis

Background: Olfactory threshold (OT) is associated with short-term inflammatory activity in relapsing multiple sclerosis (RMS). Objective: We aimed to investigate OT for prediction of treatment response in RMS. Methods: In this 5-year prospective study on 123 RMS patients, OT was measured at disease-modifying treatment (DMT) initiation (M0), after 3 months (M3), and 12 months (M12) by Sniffin’ Sticks test. Primary endpoint was defined as an absence of relapse during the observation period, with Expanded Disability Status Scale (EDSS) progression and magnetic resonance imaging (MRI) activity being the secondary endpoints. Optimal cutoff values were determined by receiver operating characteristic analyses and their predictive value assessed by multivariable Cox regression models. Results: Higher OT scores at M0, M3, and M12 were independently associated with decreased relapse probability with the strongest risk reduction at M3 (hazard ratio (HR) = 0.44, p < 0.001). Improvement of OT scores from M0 to M3 (ΔOTM3) was also associated with reduced relapse risk (HR = 0.12, p < 0.001). OT score > 6.5 at M3 was the strongest predictor of relapse freedom (HR = 0.10, p < 0.001) with high diagnostic accuracy (positive predictive value (PPV) = 87%), closely followed by ΔOTM3 ⩾ 0.5 (HR = 0.12, p < 0.001, PPV = 86%). Conclusions: OT is an independent predictor of freedom of disease activity upon DMT initiation within 5 years and may be a useful biomarker of treatment response.

Immune response to the third COVID-19 vaccine dose is related to lymphocyte count in multiple sclerosis patients treated with fingolimod.

BackgroundThe majority of multiple sclerosis [MS] patients treated with fingolimod fail to develop a protective level of IgG humoral and adaptive cellular immune responses following full BNT162b2 SARS-CoV-2 vaccination.ObjectiveTo compare the efficacy of the third COVID-19 vaccine dose in vaccine non-responders fingolimod-treated MS patients.Study designThis is a prospective 3-month, single-center, randomized clinical trial.MethodsTwenty relapsing MS patients who had been on fingolimod therapy ≥ 12 months and failed to develop humoral IgG immune response to 2-dose Pfizer BNT162b2 COVID-19 vaccination were randomized into two groups: fingolimod-continuation group and fingolimod-discontinuation group. Humoral and memory cellular immune responses were assessed within 1 and 3 months following the third Pfizer BNT162b2 vaccine dose and compared between the groups.ResultsA higher rate of patients in the fingolimod-discontinuation group [n = 8/10] compared to fingolimod-continuation group [n = 2/10] developed positive SARS-COV-2 IgG. Median IgG titer 1 month following the third dose was 202.3 BAU/ml vs. 26.4 BAU/ml, respectively, p = 0.022. The development of IgG humoral response correlated with absolute lymphocyte count. Specific SARS-COV-2 memory B cell and T cell immune responses were not detected in both groups, either at 1 month or 3 months following the third COVID-19 vaccine dose.ConclusionsShort period of fingolimod treatment discontinuation was associated with the development of humoral protection but not with adaptive cellular immunity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-022-11030-0.

Effects of COVID-19 on Multiple Sclerosis Relapse: A Comprehensive Review

Multiple Sclerosis is a chronic inflammatory disease. It is characterized by demyelinating lesions throughout the central nervous system. Patients suffering from multiple sclerosis constitute a vulnerable population to coronavirus disease-2019. This review focuses on the effects of coronavirus disease-2019 on relapse and symptom exacerbation in multiple sclerosis patients and their treatment. It highlights how the blood-brain barrier may be compromised by severe acute respiratory syndrome coronavirus 2, allowing inflammatory mediators and lymphocytes to infiltrate the central nervous system. This may increase the risk of relapse in multiple sclerosis patients. Also, in patients who did not have a prior history of multiple sclerosis, coronavirus disease-2019 has been found to impact multiple sclerosis onset and pathogenesis. However, more comprehensive research is required to fully understand the interplay between multiple sclerosis and coronavirus disease-2019.

Characterizing the time course of cerebrovascular reactivity in multiple sclerosis.

Changes in cerebral perfusion occur early in relapsing and progressive multiple sclerosis (MS) patients, though whether cerebral blood flow (CBF) can be altered by therapy is unknown. We sought to characterize the time course of change in CBF (cerebral vascular reactivity [CVR]), following intravenous (IV) acetazolamide (ACZ) in whole brain and within various gray and white matter brain regions in MS patients. We enrolled five relapsing MS patients on injectable therapies. Participants received a 1000mg IV bolus of ACZ and CBF was measured using pseudocontinuous arterial spin labeling MRI. To quantify differences in time course between patients, we calculated the numerical integration of CVR over time using the trapezoidal rule to estimate area under the curve (AUC(CVR) ). A change in whole brain CBF of 30%-65% was seen in all participants at 15minutes after ACZ challenge. CBF increases >20% above baseline were sustained for 90minutes within whole-brain, normal-appearing white matter and total T2-hyperintense lesioned tissue. AUC(CVR) values for both gray (cortical and deep gray matter) and white (normal-appearing and T2-lesioned) matter regions were similar between patients. Our findings show a prolonged time course in vascular reactivity after ACZ stimulus in MS patients with a similar time course for both gray and white matter brain regions, including in previously injured tissue. Our preliminary results suggest that blood flow can be augmented in the established MS lesion suggesting that even previously injured tissue might be responsive to treatment.

A novel disease specific scale to characterize the symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis: A real-world study

BackgroundFatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). ObjectiveTo measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). MethodsThis ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients’ lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. Results300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): mean±SD symptom score of 54.6 ± 17.8 vs. 67.0 ± 19.7, p< 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean ± SD symptom score of 62.8 ± 16.9 vs. 52.1 ± 19.3, p< 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2 ± 19.2 vs. 55.9 ± 18.6; p< 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. ConclusionFatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.

Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis

BackgroundStrategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation.ObjectiveTo provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients.MethodsWe reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation.ResultsYounger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity.ConclusionIn a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients.

Real world comparison of teriflunomide and dimethyl fumarate in naïve relapsing multiple sclerosis patients: Evidence from the Italian MS register

BackgroundTeriflunomide (TERI) and dimethyl fumarate (DMF) are licensed as first-line disease-modifying treatments (DMTs) for relapsing remitting Multiple Sclerosis (RRMS) and are largely replacing injectable DMTs. MethodsAll RRMS patients starting TERI or DMF between January 1, 2013, and December 31, 2017, were included in the analysis. Time to first relapse, time to confirmed disability progression (CDP), and time to DMT discontinuation have been investigated. Propensity score with inverse probability treatment weighting (IPTW-PS) was used to adjust comparisons for baseline confounders. The aim of the study was to compare the effectiveness, and rate of discontinuation of TERI and DMF as first therapeutic choice in the Italian MS register. ResultsA total of 683 patients were considered for the analyses, 185 on TERI and 498 on DMF. Patients on TERI had higher number of relapses (2.3 ± 1.4 vs 1.9 ± 1.1, p=.033) and higher baseline disability level assessed by Expanded Disability Status Scale (EDSS) (2.0, interquartile range-IQR 1.0–3.0 vs 1.5, IQR 1.0–2.0, p=.013). IPTW adjusted Cox models did not reveal any difference between the investigated DMTs for the investigated outcomes. ConclusionsTERI and DMF have similar effectiveness and rate of discontinuation when employed as first therapeutic choice in RRMS patients.

POSC400 Epidemiology and Patients' Characteristics in Multiple Sclerosis: An Analysis from the Italian Multiple Sclerosis Registry

This study aims at assessing prevalence, clinical, therapeutic characteristics of relapsing multiple sclerosis (RMS) patients in the Italian Multiple Sclerosis Registry (IMSR), to evaluate the percentage of patients that switch DMT due to changes in disease activity (relapses and/or evidence of new MRI activity in 2 years before data extraction) in RMS patients and describe the different drivers of therapy switch that occurs during disease course.

T-Cell Response against Varicella Zoster Virus in Patients with Multiple Sclerosis during Relapse and Remission.

An association between varicella zoster virus (VZV) and multiple sclerosis (MS) has been reported in Mexican populations. The aim of this study was to compare the response of T cells from MS patients, during relapse and remission, to in vitro stimulation with VZV, adenovirus (AV) and Epstein–Barr virus (EBV). Proliferation and cytokine secretion of T cells from 29 relapsing-remitting MS patients and 38 healthy controls (HC) were analyzed by flow cytometry after stimulating with VZV, AV or EBV. IgG and IgM levels against VZV and EBV were quantified using Enzyme-Linked Immunosorbent Assay. Relapsing MS patients showed a higher percentage of responding CD4+ and CD8+ T cells against VZV compared to AV. In HC and remitting MS patients, proliferation of CD4+ T cells was higher when stimulated with VZV as compared to EBV. Moreover, T cells isolated from remitting patients secreted predominantly Th1 cytokines when cell cultures were stimulated with VZV. Finally, high concentration of anti-VZV IgG was found in sera from patients and controls. The results support previous studies of an VZV-MS association in the particular population studied and provide additional information about the possible role of this virus in the pathogenesis of MS.

CD8+ cell somatic mutations in multiple sclerosis patients and controls-Enrichment of mutations in STAT3 and other genes implicated in hematological malignancies.

Somatic mutations have a central role in cancer but their role in other diseases such as common autoimmune disorders is not clear. Previously we and others have demonstrated that especially CD8+ T cells in blood can harbor persistent somatic mutations in some patients with multiple sclerosis (MS) and rheumatoid arthritis. Here we concentrated on CD8+ cells in more detail and tested (i) how commonly somatic mutations are detectable, (ii) does the overall mutation load differ between MS patients and controls, and (iii) do the somatic mutations accumulate non-randomly in certain genes? We separated peripheral blood CD8+ cells from newly diagnosed relapsing MS patients (n = 21) as well as matched controls (n = 21) and performed next-generation sequencing of the CD8+ cells’ DNA, limiting our search to a custom panel of 2524 immunity and cancer related genes, which enabled us to obtain a median sequencing depth of over 2000x. We discovered nonsynonymous somatic mutations in all MS patients’ and controls’ CD8+ cell DNA samples, with no significant difference in number between the groups (p = 0.60), at a median allelic fraction of 0.5% (range 0.2–8.6%). The mutations showed statistically significant clustering especially to the STAT3 gene, and also enrichment to the SMARCA2, DNMT3A, SOCS1 and PPP3CA genes. Known activating STAT3 mutations were found both in MS patients and controls and overall 1/5 of the mutations were previously described cancer mutations. The detected clustering suggests a selection advantage of the mutated CD8+ clones and calls for further research on possible phenotypic effects.