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ObjectiveTo establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS).MethodsWe long-listed licensed drugs with evidence of human safety, blood–brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review.ResultsFrom a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine.ConclusionsWe report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.

ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene–environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene–environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

ObjectiveTo assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.MethodsWe compared screening (day −14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years.ResultsThe mean PASAT score at screening was 45.38, increasing on average by 3.18 from day −14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates.ConclusionsShort-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.

ObjectivesThe aims of this manuscript were to review the evidence for the efficacy and safety of cladribine in multiple sclerosis (MS) and to review the molecular and cellular mechanisms by which cladribine acts as a disease-modifying therapy in MS.MethodsThis is a narrative review of the available clinical and preclinical data on the use of cladribine in MS.ResultsClinical trial data argue strongly that cladribine is a safe and effective therapy for relapsing MS and that it may also be beneficial in progressive MS. The pharmacology of cladribine explains how it is selectively toxic towards lymphocytes. Immunophenotyping studies show that cladribine depletes lymphocyte populations in vivo with a predilection for B cells. In vitro studies demonstrate that cladribine also exerts immunomodulatory influences over innate and adaptive immunity.ConclusionsCladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine’s action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.

ObjectiveThe PREDICT-PD study aims to identify increased risk of Parkinson’'s disease (PD) using online assessments of previously identified risk and early features of PD and an evidence-based scoring algorithm. We sought to determine whether higher risk participants (defined as those above the 15th centile of risk estimates) were more likely to have mild parkinsonian signs compared with lower risk participants.MethodsVideo recordings of neurological examinations, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, of 208 individuals who had previously completed an online risk assessment were scored blindly and independently by two movement-disorders experts. Higher risk and lower risk subjects were compared for MDS-UPDRS part III score (and derivations of this) to identify subclinical parkinsonism, and association of risk estimates with MDS-UPDRS III scores assessed.ResultsHigher risk subjects had significantly higher median UPDRS part III scores (3, IQR 1–5.5) than lower risk subjects (1, IQR 0–3.0; p<0.001), and there was a significantly greater proportion of individuals classified as having subclinical parkinsonism. 18% of the higher risk subjects and 6% of the lower risk subjects exceeded the most stringent published cut-off for subtle parkinsonism of three definitions examined (p=0.027). Linear regression analysis demonstrated a continuous relationship of log-transformed risk estimates with UPDRS part III scores (increase in MDS-UPDRS per doubling of odds 0.52, 95% CI 0.31 to 0.72; p<0.001), which remained after adjustment for multiple vascular risk factors and scores on the Montreal Cognitive Assessment (0.58, 95% CI 0.30 to 0.87; p<0.001).ConclusionsThe PREDICT-PD algorithm identifies a population with an increased rate of motor disturbances.

Predicting clinical outcome in multiple sclerosis (MS) remains challenging, and biomarkers capable of providing prognostic information would be valuable in shaping therapeutic decisions. Neurofilament light (NfL) measurements have shown promise in predicting clinical outcomes in MS. We evaluated the relationship between serum NfL (sNfL), measured at diagnosis in 164 people with MS, with contemporary disability, short-term (1-year) and medium-term (5-year) clinical outcomes. Analyses were adjusted for relevant confounders. sNfL concentration at diagnosis was modestly but significantly associated with baseline EDSS score (B=0.264, 95% CI 0.043 to 0.485, p=0.020). However, no significant associations were found between baseline sNfL and the incidence of relapse at 12-months, time to sustained accumulation of disability or 5-year change in EDSS. Dichotomising baseline sNfL according to previously cited cut-offs ( 14.2pg/ml and 90th percentile for age) did not change these results. sNfL appears to be of limited clinical utility in predicting future irreversible neurological disability, in a largely treated population, and remains insufficiently validated to shape treatment decisions at the time of diagnosis. Further studies exploring the value of sequential sNfL measurement and developing valid, universally accepted cut-offs are needed before sNfL can be incorporated as a prognostic marker in the clinic.tallantyreec@cardiff.ac.uk

Question: Does genetic risk modify the effect of environmental MS risk factors?MethodsCase-control study of 2151 people with MS and 486,125 controls using data from a longitudinal cohort (UK Biobank). MS was defined using ICD-coding or self-report. Associations with MS risk were quan- tified using multivariate logistic regression. Interaction between environmental and genetic risk factors was quantified using the Attributable Proportion due to interaction (AP). Model fits were quantified using Nagelkerke’s pseudo-R2 metric.ResultsExposures associated with MS were childhood obesity (OR=1.39, 95%CI 1.22–1.58), smoking (OR=1.19, 95%CI 1.07–1.33), and earlier menarche 0.95, 95%CI 0.92–0.98). The autosomal polygenic risk score (PRS) was associated with MS disease status (ORTop-vs-bottom-decile=3.93, 95%CI 3.11–4.97). There was evidence of synergistic interaction between the PRS and both childhood obesity (AP=0.111, 95%CI 0.007–0.202), and smoking (AP=0.106, 95%CI 2.24e-4 to 0.196).ConclusionsWe provide novel evidence for interaction between environmental risk factors for MS and a high burden of autosomal genetic risk. These findings have significant implications for our understanding of MS biology, and may inform targeted prevention strategies.ben.meir.jacobs@gmail.com

BackgroundEfficacy/safety of ocrelizumab in relapsing multiple sclerosis were demonstrated in the OPERA I/II (NCT01247324/NCT01412333) double-blind period (DBP). We assessed the efficacy of switching to or maintaining ocrelizumab after 4 years of the open-label extension (OLE).MethodsAt OLE commencement, patients continued ocrelizumab (OCR-OCR) or switched from interferon-β-1a to OCR (IFN-OCR). Adjusted annualised relapse rate (ARR), time-to-onset of 24-week confirmed disability progression (CDP24) and risk of requiring a walking aid (Expanded Disability Status Scale score ≥6.0) from DBP baseline were analysed.ResultsAmong IFN-OCR switchers, ARR decreased year-on-year from 0.2 in the pre-switch year to 0.04 in OLE Year 4; OCR-OCR continuers maintained low ARRs (pre-switch, 0.13; OLE Year 4, 0.05). CDP24 was lower year-on-year in OCR-OCR continuers versus IFN-OCR switchers in the pre-switch year (7.7% vs 12.0%) and at OLE Year 4 (19.2% vs 23.7%); p<0.05 all comparisons. Over the DBP and OLE, risk of requiring a walking aid was 44% lower (p=0.004) in OCR-OCR continuers versus IFN-OCR switchers.ConclusionsAfter 6 years of follow-up, rates of patients with CDP24 and risk of requiring a walking aid remained lower in earlier initiators of ocrelizumab (OCR-OCR) versus those initially receiving IFN (IFN-OCR), demonstrating maintained benefits of earlier treatment with ocrelizumab.g.giovannoni@qmul.ac.uk

IntroductionENDORSE (NCT00835770) evaluated the safety and efficacy of dimethyl fumarate (DMF) treatment for ≥10 years (Y) in relapsing-remitting MS (RRMS) patients.MethodsPatients treated continuously with DMF 240 mg BID in DEFINE/CONFIRM and ENDORSE were assessed for relapse, confirmed disability progression (CDP), serious adverse events (SAEs), and patient- reported outcomes (PROs): (36-item short form health survey [SF-36]; 5-dimension QoL [EQ-5D]).ResultsOf 618 patients treated for ≥10Y, 38%(192/501) were continuously-treated BID. Mean (SD) age 41.6 (8.7) Y; 68% female. Most (51%[98/192]) patients remained relapse-free or had ≤1 relapse, 73%(141/192); median time-to-first-relapse was 58 weeks. Mean baseline (SD) EDSS score was 2.24 (1.18); patients with EDSS ≤3.5: Y2 89%(164/184), Y8 80%(148/184), Y10 79%(146/184). From Y0–10, 64%(122/191) patients had no CDP. Seventy-seven (40%) patients experienced SAEs; primarily MS relapse 18%(34/192) or infections 6%(12/192). From Y0–10, serious infection incidence did not increase and SF-36 and EQ-5D remained stable.ConclusionsPatients continuously treated with DMF BID for ≥10Y had low incidence of relapses; the pro- portion of patients with EDSS ≤3.5, patients with CDP, PROs, and incidence of serious infections remained stable over 10Y reinforcing the safety and efficacy of long-term DMF treatment for RRMS patients.SupportBiogen; disclosures detailed on poster.g.giovannoni@qmul.ac.uk

IntroductionPeople with multiple sclerosis (PwMS) commonly describe being diagnosed with MS as traumatic. We did a web survey of pwMS to ascertain how many have symptoms compatible with post- traumatic stress disorder (PTSD) and how many have been diagnosed with PTSD.MethodsA web survey was conducted from the 18-Dec-20 to the 4-Jan-21 via the shift.ms platform. Shift. ms is a social network of 38,000 pwMS. Data were collected anonymously.Results1079 pwMS (78% female, mean age of 48.3yrs) with an average disease duration since diagnosis of 15.7yrs completed the survey. 58.1% of respondents reported symptoms associated with PTSD in relation to MS. Only 18.1% of respondents had received a formal diagnosis of PTSD. Comments highlighted how the diagnosis of MS was given by a healthcare professional (HCP) as being a major factor in triggering PTSD-like symptoms.ConclusionsPTSD-like symptoms and PTSD are common in pwMS and may be attributable to the way the diagnosis of MS is made. It is important that HCPs are aware of this problem and use empathetic com- munication techniques to try and mitigate against PTSD in this vulnerable group of people.g.giovannoni@qmul.ac.uk87

IntroductionEarly identification of individuals at high-risk of Parkinson’s disease (PD) may allow for the use of disease modifying treatments. We aimed to define those at risk of incident PD through environmental and genetic risk factors, comorbidities and prodromal symptoms of PD.MethodsWe identified incident cases of PD (n=1276) in the UK Biobank and unmatched controls without a PD diagnosis (n=500,406). Odds ratios for a range of determinants were calculated. A non-genetic model and polygenic risk score (PRS) were constructed. Basic gene-environment interactions were explored.ResultsStrong evidence of association (FDR < 0.05) was found between PD and family history of PD or dementia, not smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals in the top PRS decile had an increased risk of PD compared to those in the lowest decline and high scores were associated with an earlier age of diagnosis. There was evidence for a strong interaction between diabetes and PRS.DiscussionWe report the novel finding of a strong association between earlier menarche and increased PD. Analysis of gene-environment interactions found strong evidence that the effect of diabetes is modified by genetic risk. Replication and understanding the mechanism of this observation is an important next step.d.belete@nhs.net

Hedonistic homeostatic dysregulation is a neuropsychological behavioural disorder associated with substance misuse and addiction. The disorder has been recognised as a consequence of dopamine replacement therapy (DRT) in 15 patients with Parkinson's disease. The syndrome typically develops in male patients with early onset Parkinson's disease, and can occur with orally and subcutaneously administered DRT. These patients take increasing quantities of their DRT, despite increasingly severe drug induced dyskinesias, and may develop a cyclical mood disorder with hypomania or manic psychosis. There is impairment of social and occupational functioning. Tolerance develops to mood elevating effects of DRT and a negative affective withdrawal state occurs if the drugs are withdrawn or doses decreased. The clinical features and guidelines for managing this syndrome are discussed. A set of diagnostic criteria for further investigating this condition is proposed.

Background“Hit hard and early” describes first-line use of highly-effective disease-modifying treatment (HE-DMT) in people with multiple sclerosis (pwMS). However, even in treatment-active centres, months pass from diagnosis to HE-DMT losing potentially precious time to facilitate repair and protect CNS tissue from further damage. Diagnostic uncertainty contributes to hesitancy of using HE-DMT acutely. Natali- zumab (Tysabri®) is a rapidly acting HE-DMT with favourable short-term risk profile and fast elimination.AimsTo establish feasibility to enrol people within 14 days of onset of demyelination; to test Tysabri over 24 weeks for safety, efficacy, and to advance mechanistic understanding.MethodsRandomised, double-blind, placebo-controlled phase IIa trial to establish efficacy superiority over placebo at 12 weeks in facilitating remyelination CNS lesions measured using magnetisation transfer ratio. To detect 50% remyelination with 90% power at 5% significance level and 10% drop-out, n=20 par- ticipants per arm will be recruited across three UK sites.ResultsA favourable REC opinion (IRAS #1003822) has been obtained; the trial is due to start recruitment in March 2022. PPI of recently diagnosed pwMS revealed strong support of AttackMS.ConclusionsAttackMS will be the first trial of HE-DMT in people with a first event of demyelination, in a hyper-acute setting.

BackgroundNatalizumab every-6-week (Q6W) dosing is associated with lower progressive multifocal leukoencephalopathy risk than every-4-week dosing (Q4W) in retrospective analyses. NOVA is the first randomised trial to assess Q6W efficacy.ObjectiveEvaluate natalizumab Q6W efficacy in patients previously treated with natalizumab Q4W for≥12 months compared with continuation of Q4W over 72 weeks.MethodsNOVA is a randomised, controlled, open-label, rater-blinded phase 3b trial. Included patients were treated with natalizumab Q4W without relapse for ≥12 months. Patients were randomised 1:1 to Q4W (n=248) or Q6W (n=251). The primary endpoint was new/newly enlarging T2 (N/NET2) lesions. Secondary endpoints included clinical and safety outcomes.ResultsProportions of patients with N/NET2 lesions were low in both arms (Q4W:4.1%; Q6W:4.3%). Differ- ences in mean N/NET2 lesions for Q4W and Q6W (primary estimand: 0.05 vs 0.20 [P=0.0755]; secondary estimand: 0.06 vs 0.31 [P=0.0437]) were driven by two Q6W patients with extreme (≥25) values. Secondary outcomes were similar for Q4W and Q6W.ConclusionsOverall, NOVA data suggest most patients stable on natalizumab Q4W can switch to Q6W without clinically meaningful loss of efficacy. Support: Biogen. Disclosures on poster.

AimTo evaluate changes in retinal thickness (µm), including the retinal nerve fibre layer (RNFL) and combined ganglion cell and inner plexiform layers (GCIPL), in patients receiving siponimod or placebo.MethodsChanges in optical coherence tomography (OCT) measurements from screening to M12 and M24 were compared between the two treatment groups using mixed models for repeated measures adjusted for treatment, age, sex and respective baseline OCT variables.ResultsThe OCT sub-study included 159 patients (siponimod, n=104; placebo, n=55). RNFL thickness at M12 numerically favoured siponimod (0.39 vs −0.99; p=0.099) but not at M24 (−0.05 vs. 0.48; p=0.642). However, fewer assessments were available for RNFL at M24 than M12. The between-group difference in GCIPL thinning was 0.21 (−2.55 vs −2.76; p=0.875) at M12 and 3.82 (−0.47 vs −4.29; p=0.01) at M24. Siponimod reduced retinal thinning vs placebo at M12 (change from baseline: 0.66 vs −1.86; p=0.006) and M24 (−0.05 vs −2.3; p=0.033). Changes of retinal thickness and GCIPL at the subfield areas also favoured siponimod over placebo.ConclusionsThese results support the sensitivity of OCT as a measure of tissue damage in progressive MS and are in line with previously reported beneficial effects of siponimod on other neurodegeneration related outcomes. Funding: Novartis Pharma AG, Basel, Switzerland.

ObjectiveTo evaluate the contribution of MRI activity and relapses in defining disease activity in Secondary progressive multiple sclerosis (SPMS) patients by analysing real-world data from Adelphi real-world MS Disease Specific Programme (Adelphi-MS-DSP) and to understand whether active SPMS (aSPMS) and non-active SPMC (naSPMS) are mutually exclusive groups in EXPAND.MethodsAdelphi-MS-DSP was a non-interventional, multinational real-world study (N=37,318). Patients were categorised into aSPMS (⩾1 new lesion on the most recent MRI and/or ⩾1 relapse in the last 12-months) and naSPMS groups. In EXPAND, disease activity was defined as relapses in the 2-years before screening and with/without ⩾1 gadolinium-enhancing (Gd+) T1 lesion at baseline. Demographics, MRI and relapse status were analysed descriptively.ResultsSPMS from the Adelphi-MS-DSP were categorised as aSPMS (n=1889) and naSPMS (n=665). Disease activity for aSPMS was based on MRI lesions (59.1%), relapses (12.6%), and both (28.3%). In EXPAND, 52.6% of patients (n/N=866/1645) who had no relapse in the 2-years prior to screening and no Gd+ T1 lesions at baseline were categorised under naSPMS; of these who were on placebo, 52.7% experienced on-study relapse and/or MRI activity.ConclusionsIn both real-world and clinical studies, MRI activity appears to be a more sensitive measure of disease activity versus relapses. Funding: Novartis Pharma AG, Basel, Switzerland.

BackgroundIn the Phase 3 EXPAND study, siponimod reduced the Neurostatus-EDSS-measured risk of 3/6-month (M) confirmed disability progression versus placebo by 21%/26%, with more pronounced effects (31%/37%) in active SPMS (aSPMS). Here we evaluated the contribution of the Ambulation Score (AS) to measuring siponimod’s effect on disability progression.Design/MethodsThis post-hoc analysis included the overall population (OP); siponimod/placebo n=1099/546) and aSPMS/non-active (naSPMS) patients (siponimod, n=516/557; placebo, n=263/270). Outcomes included change from baseline in Neurostatus-EDSS/AS, time-to-first worsening on AS (3M/6M confirmed worsening [3M/6MCW]) by ≥1/≥2-points and categorical analysis (proportion of patients with 3M/6MCW or confirmed improvement [CI] by ≥1-point during the core study [median(range): 21(0.2–37.0) M]).ResultsIn the OP, the Neurostatus-EDSS, and more prominently, AS change from baseline, favored siponimod versus placebo at all visits (M6-M30); most pronounced at M18 (EDSS: 0.13 versus 0.23;p=0.003; AS: 0.50 versus 0.81;p=0.001). Siponimod significantly reduced the risk of 3MCW (≥1-point, HR=0.78,p=0.0046;≥2-point, 0.71,p=0.0007) and 6MCW in AS (≥1 point, 0.74, p=0.0023).In aSPMS, pronounced effects were observed in 3MCW (≥1-point, HR=0.68,p=0.002; ≥2-point, 0.60,p=0.0005); 6MCW (≥1-point, HR=0.63,p=0.0007), with fewer patients worsening/more improving on siponimod and a trend for fewer patients worsening in naSPMS.ConclusionsMore pronounced effects on the Neurostatus-EDSS and AS were observed in aSPMS. Funding: Novartis Pharma AG, Basel, Switzerland.

ObjectiveAssess the predictive value of cognitive processing speed (CPS), using the Symbol Digit Modali- ties Test (SDMT) score, on disability progression in secondary progressive multiple sclerosis (SPMS).Design/MethodsSPMS patients from the Phase 3 EXPAND study (core part [CP] and core+extension part [CP+EP]) were categorised into quartiles of baseline SDMT score (worst-WQ [Q1], intermediate [Q2-Q3], and best-BQ [Q4] quartile). The predictive value of baseline SDMT quartiles for time-to-wheelchair (T2W; i.e., Expanded Disability Status Scale [EDSS] score ≥7) sustained until end of follow-up, or 6-month confirmed disability progression (6mCDP) by EDSS, were assessed at the end of the CP (up to 37-months) and CP+EP (up to 5-years) by Cox regression (adjusted for treatment, age, gender, baseline EDSS, baseline SDMT quartile, and treatment-by-baseline SDMT quartile interaction).ResultsAnalyses included 1628/1651 patients (98.6%) randomised in EXPAND (baseline SDMT: WQ, n=435; intermediate, n=808; BQ, n=385). Risk of T2W (WQ vs BQ) was higher in the CP (HRWQ/BQ=1.31, 95% CI:0.72–2.38; p=0.37) and increased with long-term follow-up (HRWQ/BQ=1.81; 1.17–2.78; p=0.01). Baseline SDMT was not predictive of 6mCDP. The predictive value of on-study SDMT score change will be presented.ConclusionsThe results support the predictive value of CPS for long-term physical disability progression in SPMS. Funding: Novartis Pharma AG, Basel, Switzerland.

Genome-wide association studies (GWAS) of Multiple Sclerosis (MS) have focussed on populations of European ancestry. Studying MS genetics in other ancestries is necessary to ensure the generalisability of these findings.We report the design of a new collaborative MS genetics project – ‘ADAMS’. Individuals with MS from non-White-British ethnic backgrounds will be recruited either via a website – https://app.mantal.co.uk/ adams – or in-person at a participating site. We will collect demographic and phenotypic data using a combination of a baseline questionnaire and subsequent healthcare record linkage. We will collect DNA from up to 1000 participants using saliva kits (Oragene-600) and genotype individuals using the Illumina Global Screening Array version 3. Genotypes will be combined with large ancestrally-matched control datasets (UK Biobank and East London Genes and Health).We have recruited 91 participants within the first eight weeks of the study. Of this initial cohort, 73.9% are female, 84.5% were born in the UK, 32.4% identified as Asian or Asian British, 28.2% as Black, African, Caribbean or Black British, and the remainder identified as having mixed, other, or White backgrounds. 51% stated they were unlimited in their mobility. 84.7% of participants have relapse-onset forms of MS and 76.1% have ever had disease-modifying therapy. The median age at diagnosis is 30.5 and the median age at recruitment 36.7. Further recruitment and genetics results will follow over the next 3 years.

IntroductionA range of non-motor features can be evident at the point of diagnosis of Parkinson’s disease (PD).ObjectivesTo identify non-motor features of prodromal PD in participants from the PREDICT-PD study.MethodsHigher-risk (HR) (odds of PD >1:30) and matched lower-risk (LR) participants from PREDICT-PD and PD patients underwent validated clinical assessments, in which the assessor was blinded to risk scores, including MDS-UPDRS I-III, other functional motor tasks, and standardised assessments of cognition, autonomic function, pain and sleep.Results28 LR, 31 HR and 22 PD patients were examined. HR participants were more impaired than LR in all motor tasks, as well as the SCOPA-AUT, PD Sleep scale, HADS and MDS-UPDRS I & II. There were no sig- nificant differences between HR and PD, other than for the MDS-UPDRS part II, part III, the gastrointestinal sub-score of the SCOPA-AUT, and measured orthostatic hypotension. In all domains tested there was a relationship between the log odds of PD risk and dysfunction using linear regression.ConclusionThis study provides strong evidence that non-motor features are prominent in at-risk indi- viduals, as well as mild motor impairment, and that these symptoms and signs are similar to patients with established PD. Further follow-up will establish which patients develop the cardinal motor signs necessary for a clinical diagnosis of PD.

IntroductionTranscranial sonography (TCS) has been shown to be a reliable imaging biomarker in patients with Parkinson’s disease (PD). 90% of patients with PD have enlarged nigral hyperechogenicity (SN+) compared to 10% healthy controls (HC).ObjectiveTo assess the relationship between SN+ and motor and non-motor features of prodromal PD.MethodsHigher-risk (HR) and lower-risk (LR) age- and gender-matched controls from the PREDICT-PD study were compared alongside PD patients. TCS was performed with a cut-off of 0.20cm2 for SN+. Validated scales were used to assess motor and non-motor features. All assessments were undertaken blind to risk of PD determined by the PREDICT-PD algorithm. PREDICT-PD participants were compared according to enlarged or normal SN echogenicity.Results47 PREDICT-PD participants and 13 PD patients were compared. 40/47 PREDICT-PD participants and 12/13 PD patients had good quality sonographic appearances on at least one side. 24 PREDICT-PD participants had enlarged SN+ and 23 were normal. SN+ participants had higher MDS-UPDRS III scores than those with normal SN (mean 6 vs 4, p=0.036), but did not differ in any other domain. There was no relationship between SN+ and risk of PD.ConclusionDespite evidence for use around the time of PD diagnosis in individuals with motor features of PD, we found no convincing evidence to support the use of TCS in the prodromal phase.

IntroductionAnosmia is common at the point of diagnosis of Parkinson’s disease (PD) and often predates motor symptoms. Other non-motor symptoms are also recognised to predate overt motor impairment in PD.ObjectiveTo identify prodromal markers of PD in patients with idiopathic anosmia (IA).MethodsPatients age >55y diagnosed with IA in sub-specialist ENT clinics were recruited to the PREDICT-PD study. We compared them with lower-risk healthy older adults (HA) in PREDICT-PD and PD patients. Par- ticipants were assessed with MDS-UPDRS I-III, as well as standardised assessments of cognition, autonomic function, pain and sleep. The IA group were split into those with mild motor impairment (IA-MMI) and normal motor function (IA-NM), and the comparisons repeated.ResultsWe recruited 28 HA, 42 IA and 21 PD. The groups were well matched for age and gender. Compared with HA, IA had worse sleep (PD Sleep Scale p=0.023), depressive symptoms (HADS p=0.03) and gastrointestinal (GI) symptoms (SCOPA-AUT GI p=0.035). 23.8% of IA and 15.0% HA scored >6 on the MDS-UPDRS III (p=0.29). IA-NM did not differ from IA-MMI in any domain, including functional motor tasks.ConclusionParticipants with IA did not have demonstrable impairments in motor or non-motor tests when compared to healthy older adults, with the exception of sleep, mood and GI symptoms.

ObjectivesTo identify whether people with MS (pwMS) suffer from postprandial somnolence (PPS) more than people without MS (controls), to examine whether the severity of MS is correlated to the severity of PPS and to describe strategies pwMS are using to reduce their symptoms of PPS.BackgroundpwMS might be more sensitive to PPS, but no studies confirming this association have been published.MethodsA cross-sectional study was conducted among pwMS at The Royal London Hospital, London. Patients and controls completed an online survey including demographics, comorbidities and Stanford Sleepiness Score (SSS) one hour after lunch.ResultsSurvey responses of 77 pwMS (mean age 45.3 ± 11.5 years; 62.3% female) and 37 controls (mean age 47.02 ± 13.9 years; 63.8% female) were obtained. The mean SSS for pwMS was 3.46 ± 1.67, whilst the mean SSS for controls was 2.52 ± 1.18 (p=0.001). No linear correlation was observed between EDSS and SSS (R2=0.011). 63% of pwMS reported making self-administered changes to their diet to help their symptoms.ConclusionsPwMS were affected by PPS more than controls. EDSS was not predictive of PPS severity in pwMS. pwMS are adopting self-management strategies to reduce their symptoms of PPS.tatiana.christmas@nhs.net

BackgroundThis post-hoc analysis evaluated long-term disease stability of relapsing-remitting multiple sclerosis (RRMS) patients, according to Expanded Disability Status Scale (EDSS), after treatment with clad- ribine tablets 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) in CLARITY and CLARITY Extension.MethodsPatients randomised to CT3.5 in CLARITY then placebo in CLARITY Extension, with ≥1 post- baseline EDSS measurement, were included (CP3.5, n=98). EDSS score over time (CLARITY randomisation to end of follow-up in CLARITY Extension, including the bridging interval between studies) was assessed at 6-month intervals, and separately at time to 3- and 6-month confirmed EDSS score progression from CLARITY baseline.ResultsFive years after CLARITY baseline, median EDSS remained stable compared with baseline. Median EDSS score (95%CI) for CP3.5 was 2.5(2.0–3.5) vs 3.0(2.5–3.5) at baseline. In each 12-month period, EDSS score was stable in >50% of patients, 21–30% improved and 0–25% worsened. During Year 5, EDSS was stable in 53.9% of patients, 21.3% improved and 24.7% worsened; <30% of patients reached 3- or 6-month confirmed EDSS progression.ConclusionsEDSS score was stable up to 5 years post-CLARITY baseline for CP3.5 patients. Between 20–30% of patients demonstrated improvement in EDSS score vs baseline each year. CLARITY: NCT00213135.CLARITY ExtensionNCT00641537g.giovannoni@qmul.ac.uk

BackgroundGrey matter (GM) loss is associated with cognitive decline and physical disability in multiple sclerosis (MS). In Phase 3 EXPAND study, siponimod significantly reduced disability progression, cognitive decline and whole brain volume loss in patients with secondary progressive MS (SPMS).MethodsMagnetic resonance imaging (MRI) from EXPAND were pooled and analysed using high reso- lution T1 and conventional MRI. Analysis included intent-to-treat population (full analysis set, FAS) and per protocol set (PPS). Change from baseline in cortical grey matter (cGM) and thalamic volumes were assessed.ResultsIn the FAS, adjusted mean percent change in volume from baseline at M12 and M24, respectively, was −0.07 versus −0.59 (88% reduction vs placebo, p<0.0001) and −0.51 versus −0.90 (43% reduction; p<0.0001) for cGM; −0.54 versus −1.01 (47% reduction; p< 0.0001) and −1.20 versus −1.74 (31% reduction; p=0.0001) for the thalamus. PPS values were 0.01 versus −0.60 (100% reduction; p< 0.0001) and −0.39 versus−1.04 (63% reduction; p< 0.0001) for cGM; −0.47 vs −0.94 (50% reduction; p< 0.0001) and −1.02 versus −1.77 (42% reduction; p< 0.0001) for the thalamus.ConclusionsSiponimod significantly reduced cGM and thalamic volume loss compared with placebo in patients with SPMS.g.giovannoni@qmul.ac.uk

BackgroundSiponimod, a selective sphingosine 1-phosphate receptor modulator, demonstrated clini- cally relevant effects in a typical secondary progressive multiple sclerosis (SPMS) population in the Phase 3 EXPAND study, with 21% and 26% reductions in 3- and 6-month confirmed disability progression (CDP) versus placebo.MethodsPost hoc subgroup analysis was performed in patients with active disease (defined as the presence of relapses in 2 years before screening and/or ≥1 T1 gadolinium-enhancing [Gd ] lesion at baseline) to assess the efficacy of siponimod 2mg versus placebo in this population. ResultsThis analysis included 779 SPMS patients with active disease (siponimod [n=516], placebo [n=263]). The proportion of patients with relapse in the 2 years prior to study was 76% and with Gd lesions at baseline 45%. Siponimod significantly reduced 3-month CDP risk by 31% (HR [95% CI]: 0.69 [0.53, 0.91]; p=0.0094) and 6-month CDP risk by 37% (HR [95% CI]: 0.63 [0.47, 0.86], p=0.0040) versus placebo. Reductions in risk of 6 month SDMT worsening, ARR, and MRI endpoints were also seen.ConclusionsIn this subgroup of active SPMS patients from EXPAND, benefits on disability progression were more pronounced with clinically relevant effects across disability progression, cognitive processing speed, and MRI inflammatory disease activity.g.giovannoni@qmul.ac.uk

IntroductionCladribine tablets (Mavenclad®) are licensed for treating people with relapsing multiple sclerosis (pwRMS). We treated people with relapsing (pwRMS) and progressive MS (pwPMS) using sub- cutaneously administered cladribine (SCAC) since 2014. Here, we present up to five year follow-up on safety and efficacy.MethodsSCAC 10mg was given on 3–4 days during week 1. 0–3 doses were administered at week 5, according to week 4 lymphocyte count. A second cycle of SCAC was administered 11 months later. Follow-up included clinical outcome evaluation and pharmacovigilance. The proportion of pwMS with no evidence of (i) disease activity (NEDA) and (ii) progression or active disease (NEPAD) was calculated.Results211 pwMS received SCAC. 154/211 completed two treatment cycles. At baseline age was 44 (17–72) years, EDSS 1–8.5. Tolerability was good. One myocardial infarction and one breast cancer occurred. Two severely disabled pwMS died (one of influenza, one of encephalitis). Lymphopenia grade 3 was detected in <3%. At 2 years, 71% (CI 54%, 85%) of pwRMS had NEDA; 38% (CI 23%, 54%) of pwPMS had NEPAD.ConclusionsSCAC was well tolerated. Frequency of significant lymphopenia was low. Efficacy in pwRMS corresponds with trial data. NEPAD rates in pwPMS were similar to licensed DMT.k.allen-philbey@nhs.net

BackgroundThis analysis updates on the previously reported serious treatment emergent adverse event (TEAE) profile of cladribine tablets (CT) 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) following integration of final data from the PREMIERE registry and post-approval safety data from worldwide sources.MethodsThe monotherapy oral cohort (CT3.5, N=923, patient-years [PY]=3936.69; placebo, N=641, PY=2421.47) was derived from the CLARITY, CLARITY Extension and ORACLE-MS trials plus the PREMIERE registry. Adjusted adverse event incidences-per-100PY (Adj-AE-per-100PY) were calculated, cumulative to end of PREMIERE (October 2018).ResultsPatient characteristics were balanced between groups. Adj-AE-per-100PY for ≥1 serious TEAE were:3.80 (CT3.5), 3.05 (placebo); for serious lymphopenia (preferred term [PT]): 0.10 (CT3.5), 0 (placebo); for serious infections and infestations (system organ class): 0.60 (CT3.5), 0.42 (placebo); for serious herpes zoster (PT): 0.05 (CT3.5), 0 (placebo); and malignant tumours: 0.26 (CT3.5), 0.12 (placebo). Post-approval sources reported 1622 AEs in the Periodic Benefit-Risk Evaluation Report (275 were serious); none repre- sented a new safety signal.ConclusionsNo new major safety findings for cladribine tablets were identified in this finalised integrated dataset containing final data from the PREMIERE registry. Findings are consistent with previously published integrated safety analyses. No new safety signals were identified from post-approval safety data. CLARITY: NCT00213135. CLARITY Extension: NCT00641537. ORACLE-MS: NCT00725985. PREMIERE: NCT01013350g.giovannoni@qmul.ac.uk

IntroductionNatalizumab treatment is associated with risk of progressive multifocal leukoencephalopa- thy (PML). Following PML diagnosis, plasma exchange (PLEX) may be used to enable rapid natalizumab clearance. This analysis explores the impact of PLEX and patient characteristics on natalizumab-associated PML outcomes.MethodsPatients with multiple sclerosis, natalizumab-associated PML, and PLEX treatment status as of September 2018 were included (PLEX+, n=616; PLEX−, n=109). The primary outcome was 2-year survival after PML diagnosis. Kaplan-Meier estimates of cumulative survival for patients with/without PLEX were stratified by log JC virus (JCV) viral copy number (VCN) at PML diagnosis. Hazard ratios for survival were based on a Cox proportional hazards model.ResultsThe cumulative probability of 2-year survival for PLEX+ vs PLEX− patients was 88.2% vs. 89.3% (P=0.857) with log VCN ≤5, 73.8% vs. 89.3% (P=0.097) with log VCN >5 to ≤7, and 68.2% vs. 78.9% (P=0.435) with log VCN >7. Improved survival was associated with younger age, asymptomatic presentation, localized PML lesions, and lower log JCV VCN.ConclusionsPLEX had no significant effect on survival rates. Numerically worse 2-year survival probabilities were observed with PLEX regardless of PML presentation, suggesting PLEX is not effective for improving post-PML outcomes.SupportBiogen. Disclosures: Included on the poster.g.giovannoni@qmul.ac.uk

IntroductionNo evidence of disease activity (NEDA; no relapses, MRI activity, or Expanded Disability Status Scale worsening) is considered a multiple sclerosis (MS) treatment goal. We assessed the independent contributions of NEDA components, serum neurofilament light (sNfL), brain parenchymal fraction (BPF), and other clinical outcomes in defining disease control with natalizumab.MethodsWe used AFFIRM data from 792 patients to assess change (baseline to year [Y] 2) in NEDA com- ponents, worsening of Paced Auditory Serial Addition Test, 9-Hole Peg Test, Timed 25-Foot Walk, change (Y1-Y2) in BPF, and Y2 sNfL levels. Comparisons included odds ratios (ORs) for natalizumab vs placebo and area under the receiver-operating characteristic curve (AUC).ResultsNo MRI activity (OR=9.3; AUC=0.73; P<0.0001 vs. placebo), no relapses (2.7; 0.62; P<0.0001), and sNfL <8 pg/mL (4.1; 0.67; P<0.0001) had the strongest association with natalizumab. The best-fit multivariate logistic regression model included no MRI activity (OR=7.6; 95% CI=5.0–11.5; P<0.0001), sNfL (3.1; 2.2–4.5; P<0.0001) and no relapses (2.1; 1.5–3.0; P<0.0001).ConclusionMRI activity, sNfL, and relapses had the strongest natalizumab treatment association over 2 years in AFFIRM. sNfL may be useful in defining disease control with natalizumab.*Additional authors: Richard A. Rudick (Biogen, Cambridge, MA, USA), Al Sandrock (Biogen, Cambridge, MA, USA). Support: Biogen. Disclosures: Included on poster.g.giovannoni@qmul.ac.uk

BackgroundCladribine tablets 10mg, cumulative dose 3.5mg/kg (CT3.5) over 2 years, showed efficacy vs placebo in patients with relapsing multiple sclerosis. This post-hoc analysis explored the relationship between baseline Expanded Disability Status Scale (EDSS) and risk of progression to secondary progres- sive (SPMS, EDSS ≥6.0) in CLARITY.MethodsThis analysis used a proxy composite definition of SPMS. Patients progressing to EDSS ≥6.0 were defined as ≥1 post-baseline EDSS ≥6.0 with 3- or 6-month confirmed disability progression (CDP).ResultsProxy SPMS progression was lower for CT3.5 vs placebo: overall (6.7% vs 13.5% [OR 0.46; 95%CI: 0.28–0.76]; P=0.0024); baseline EDSS ≤3.0 subgroup (3.5% vs 7.7% [OR 0.44; 95%CI: 0.19–0.99]; P=0.047]); baseline EDSS ≥3.5 subgroup (12.2% vs 22.4% [OR 0.48; 95%CI: 0.26–0.9]; P=0.0212). Patients with 3-month CDP with EDSS ≥6.0: 3.5% vs 8.0% (OR 0.42 [95%CI: 0.22–0.82]; P=0.0114); 6-month CDP with EDSS ≥6.0: 2.8% vs 5.8% (OR 0.48 [95%CI: 0.22–1.02]; P=0.0566).ConclusionsRisk of progressing to proxy SPMS within 2 years of treatment or experiencing EDSS ≥6.0 was sig- nificantly reduced with CT3.5 compared to placebo, regardless of baseline EDSS. CLARITY: NCT00213135g.giovannoni@qmul.ac.uk

IntroductionStrategy, evidence and anticipation should underpin workforce-planning.AimTo estimate a sustainable patient-caseload (PCL) for a full-time equivalent MS specialist neurologist (FTE-MSologist).MethodsHypothetically, an FTE-MSologist refers to 10-MSology-related programmed activities per week. We considered three service models (core, aspirational, alternative/DGH) with differing frequency, duration and content of patient consultations and monitoring. We computed the ideal number of new patients and existing patients, for each scenario, from detailed qualitative interviews with 4 MSologists at different NHS Trusts. Computations assumed all 3 scenarios had common support from MS nurses (@315 PLwMS/FTE MS nurse), MS coordinators, neuroradiology, neuropharmacist and administration.ResultsEstimates for 1-FTE-MSologist/year/service model were: Core: new-PCL=81 (range=46–115); existing- PCL=798 (range=672–923). Aspirational: new-PCL=21 (range=28–69); existing-PCL=481 (range=401–561). Alternative/DGH: new-PCL=89 (range=51–126); existing-PCL=874 (range=733–1015).ConclusionsThese MS PCL/FTE-MSologist estimates enable future NHS manpower planning to optimally staff specialist MS services. It is notable that few (if any) UK MS services have the support considered pre- requisite. Much of the direct clinical care work undertaken is “unseen” and not formally job-planned. These results have significant implications formal time and motion studies may be required to improve estimates’ accuracy.Support.Karen Bateman was supported by Novartis. Disclosures: See poster g.giovannoni@qmul.ac.uk

IntroductionSocioeconomic status (SES) is a major determinant of health outcomes. This study explored the relationship between SES, comorbidities, and emergency admissions in people with multiple sclerosis (pwMS).MethodsNational Health Service England data from the Hospital Episodes Statistics (HES) database were used. Socioeconomic deprivation was assessed using the English Index of Multiple Deprivation.ResultsIn 2019–2020, 6,210 of 36,765 pwMS in England (16.9%) were classified as “most deprived” (+29.1% versus 2015–2016). Of these most deprived pwMS, 17.8% had an emergency admission. Across 25 des- ignated Neuroscience Centres, the percentage of “most deprived” pwMS ranged from 3.0%-34.0% and the percentage of “most deprived” pwMS with emergency admissions ranged from 0%-47.6%. In England, diagnoses more common in emergency MS admissions (compared to all MS admissions) included pneumonia, sepsis, intestinal disorders, decubitus ulcer/pressure area, and disorders of fluid, electrolyte, and acid-base balance. Factors associated with deprivation (type 2 diabetes, hypertension, smoking) were seen across all MS admissions.ConclusionsThe proportion of “most deprived” pwMS and the proportion of “most deprived” pwMS with emergency admissions varied widely across centres. MS- and deprivation-related comorbidities were observed in emergency admissions of pwMS, highlighting the importance of addressing these issues.SupportBiogen. Disclosures: Included in poster. jean.vonsy@biogen.com85

BackgroundIn the EXPAND study, patients with active SPMS (aSPMS) demonstrated a reduced risk of 3/6-month confirmed disability progression (3m/6m CDP) and risk of decline in cognitive processing speed (CPS, 6-month confirmed cognition worsening of ≥4-point on Symbol Digit Modalities Test [6mCCW]) versus placebo.ObjectivesAssess long-term efficacy and safety of siponimod in patients with aSPMS.MethodsIn aSPMS patients who entered the EXPAND Extension, time to 3m/6mCDP, 6mCCW, and annu- alized relapse rate (ARR) were assessed for the Continuous (siponimod in Core and Extension) and Switch (placebo in Core and open-label siponimod in Core/Extension) groups.ResultsRisk of 6mCDP was reduced by 29% (0.71 [0.57–0.90]; p=0.0044) for Continuous versus Switch group, corresponding to approximately 70% delay in time to 6mCDP. The risk of 6mCCW for Continuous versus Switch group was reduced by 33% (0.67 [0.53–0.86]); p=0.0018), corresponding to approximately 70% delay in time to 6mCCW. A significant reduction in ARR for the Continuous versus Switch groups was observed in patients with or without active disease.ConclusionsLong-term data analyses showed that siponimod effects on disability, cognitive processing speed, and relapse outcomes in patients with active SPMS are sustained up to 5 years, and highlight the value of early treatment initiation.teresa.sawtell@novartis.com

BackgroundChanges in magnetization transfer ratio (MTR) are a marker of changes in myelin density and brain tissue integrity. Siponimod improved lesional MTR recovery in the overall EXPAND secondary progressive multiple sclerosis (SPMS) population.ObjectivesInvestigate the effect of siponimod on MTR changes in SPMS subgroups.MethodsThis prospective sub-study assessed the effect of siponimod versus placebo on median nor- malized MTR (nMTR) in normal appearing brain tissue (NABT), cortical Grey Matter (cGM) and normal appearing white matter (NAWM). Subgroups were defined by: disease history, severity and duration, EDSS score, Symbol Digit Modalities Test score, and inflammatory disease activity.ResultsThere was an attenuation in median nMTR decrease versus placebo across all subgroups (all p<0.05 except EDSS≥6 subgroup, p=0.064). In the active SPMS subgroup, siponimod attenuated median nMTR decrease across NABT, cGM and NAWM by 91–109% (p<0.01 all); and in the non-active SPMS subgroup by 170– 198% (p=0.0151 for NAWM, p>0.05 for NABT, cGM).ConclusionsOver 24 months, siponimod attenuated the decrease in median nMTR in brain tissues across patient subgroups characterized by disease activity and severity, with most pronounced effects in NAWM. This supports preclinical studies, showing beneficial CNS effects on myelination.teresa.sawtell@novartis.com

BackgroundSiponimod significantly reduced the relative risk of 3-month (m) confirmed disability progression (CDP) by 21% and 6mCDP by 26% versus placebo in the EXPAND core study and showed significant benefits on cognitive processing speed (CPS) using the Symbol Digit Modalities Test (SDMT).ObjectivesTo evaluate the effect of siponimod on CPS in active (aSPMS) and non-active (naSPMS) patients from EXPAND core study.MethodsThis subgroup analysis included aSPMS patients (siponimod, n=516; placebo, n=263) and naSPMS patients (siponimod, n=557; placebo, n=270). Change in SDMT score; time to 6m confirmed ≥4-points cognitive worsening/improvement (6mCW/6mCI) on SDMT and the proportion of patients with worsened, stable and improved SDMT scores at M24 were analysed.ResultsChange in SDMT (95% Cl) versus placebo from baseline to M24 in aSPMS and naSPMS groups was2.34 (0.66; 4.02) and 2.44 (0.67; 4.22), respectively, consistent with overall EXPAND core population. In aSPMS patients, siponimod reduced risk of 6mCW by 27% (p=0.06) and improved chances of 6mCI by 62% (p=0.007) versus placebo. Corresponding values in the naSPMS group were: 6mCW, 24% (p=ns) and 6mCI, 19% (p=ns).ConclusionsSiponimod was associated with relevant benefits in CPS as measured by change in SDMT in patients with active and non-active SPMS.teresasawtell@novartis.com82

BackgroundThere is an urgent need for reliable methods to remotely monitor Multiple Sclerosis (MS). Existing assessments, such as Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT), are traditionally carried out in person by physicians. The use of self-administered, remote versions of these assessments could improve monitoring and hence care for people with MS (pwMS). This study evaluated the use of remote T25FW (rT25FW) and 9HPT (r9HPT) assessments.Methods pwMS were given comprehensive instructions and equipment for completing rT25FW/r9HPT. We assessed relationships between EDSS scores (through a previously-validated webEDSS) and contem- poraneous rT25FW/r9HPT using Spearman’s rank-order correlation, to evaluate consistency with previous in-person studies.ResultsSeventy-one pwMS completed the webEDSS and r9HPT, and 108 completed the webEDSS and rT25FW. There was a mild-moderate positive correlation between webEDSS and rT25FW (rho=0.40, p<0.0001, 95%CI=0.23–0.55), a finding consistent with previous in-person studies. There was a non-significant weak correlation between webEDSS and r9HPT. Distributions of rT25FW/r9HPT times were positively skewed. 100% of r9HPT times and 93.5% of rT25FW times were within specified limits used in clinical trials.ConclusionThese findings provide pilot evidence to indicate remote monitoring of MS is feasible. These assessments should be further developed to aid remote follow-up of pwMS.ashvin.kuri99@gmail.com

BackgroundOlfactory dysfunction is an early, non-motor feature of Parkinson’s disease. The UPSIT is one of the most commonly used smell tests. However, newer methods to encapsulate smells might offer better performance and longer ‘shelf life’. We developed a prototype of a novel smell test involving microen- capsulation of essential oils (EO) in alginate gel.MethodsA dual infusion pump system with a stainless-steel nozzle needle, containing an inner and outer needle, emitted EO and alginate respectively. The alginate beads expelled from the needle were solidified in calcium chloride (CaCl2) solution (1M). Various alginate viscosities were investigated. Microcapsules were separated into 3 storage conditions: open, closed and loosely sealed (LS). Their size, weight and scent retention were monitored over six months.Results98% of LS microcapsules remained functional at six months. The average weight of microcap- sules decreased by 15.9%, reaching 0.0024g by six months. However, microcapsules made using medium viscosity (>2000cP) alginate and those kept in LS conditions, remained relatively constant in weight. Mor- phological analysis revealed the average diameter of microcapsules to be 2mm.ConclusionThis pilot project has provided insight into the microencapsulation process, indicating that medium viscosity alginate and LS storage are favourable for future development of a cheap and widely applicable smell test.ha15632@qmul.ac.uk

BackgroundUveitis describes intraocular inflammation of the uveal tract. It may be associated with auto- immune diseases (e.g. ankylosing spondylitis), inflammatory diseases (e.g. Crohn’s), infections (TB, toxoplas- mosis) or it may be idiopathic, however an association with Multiple Sclerosis (MS) has also been observed.Methods2151 individuals with MS were identified within UK Biobank via ICD-10 code G35 and self-reported diagnosis, and compared to the remainder of the Biobank cohort. Uveitis was defined using ICD-10 codes H20, H30, and H22.1 along with self-report. We used multivariate logistic regression to model uveitis diagnosis on MS status and control for confounding factors (age, sex, and socio-economic status).ResultsUveitis prevalence in people with MS was 0.60%, compared to 0.18% in controls. 3 individuals with MS and uveitis had an additional diagnosis associated with uveitis (ankylosing spondylitis and sarcoid) and were excluded, leaving a prevalence of 0.48%. The odds ratio (OR) of uveitis in MS was 2.73, 95%CI 1.46–5.10, p = 0.0068. 90% people with dual diagnosis were female. 30.0% were DRB1*15 heterozygotes, while 70.0% carried no copies of the DRB1*15 risk allele.ConclusionsThese findings support the suggested association of these two conditions and demonstrate a comparable predominance of white females with both conditions.thomasrptaylor@gmail.com

AimsTo assess the impact of the usage of atraumatic lumbar puncture needles on lumbar puncture complications across the United Kingdom, following the national atraumatic lumbar puncture needle campaign which commenced in 2015DesignA retrospective cross-sectional audit of regional datasets was employed.SubjectsAll patients undergoing a lumbar puncture for both therapeutic and diagnostic purposes at regional neuroscience centres.MethodsWe requested hospital episode statistics (HES) from all regional neuroscience centres in the United Kingdom (32 sites). Through freedom of information (FOI) requests we asked the centres to provide the number of epidural blood patches procedures, post-lumbar puncture headaches and lumbar puncture needle procurement orders over a four-year period (2015–2018). A surrogate complication rate was cal- culated by the sum of the complications divided by the total procurement orders.ResultsOf all sites 32 sites, 16 centres provided usable datasets. Between the period of 2015–2018 there was a non-significant decrease in complication rates when using atraumatic lumbar puncture needles (p=0.14).ConclusionsThe study did not show a statistically significant decrease in the complication rates over the specified period, supported by previous work suggesting poor adherence to atraumatic needle usage.ines-alsousa@hotmail.com

ObjectivesTo assess the impact of a national atraumatic lumbar puncture needle campaign on lumbar puncture needle usage across the United Kingdom. The campaign commenced in 2015, to increase usage of atraumatic needles to reduce complications associated with traumatic needles.DesignRetrospective cross-sectional auditMethodsWe requested procurement orders from all regional neuroscience centres in the United Kingdom, through freedom of information (FOI) requests to identify their lumbar puncture needle purchases over a four-year period (2015–2018). Of all sites, 20 centres provided usable datasets. Product codes were cross correlated to identify the type of lumbar puncture needle used. The procurement orders were used as a surrogate marker for lumbar puncture needle usage and to calculate a ratio of atraumatic: traumatic needles.ResultsIn total we analysed 739,209 procurement orders over the four-year period. The Atraumatic/Traumatic needle ratio was 0.244 ± 0.039 in 2015 and increased to 0.276 ± 0.046 in 2016 (p=0.05), witha subsequent decrease in 2017 to 0.252 ±0.042 (p=0.37) and 2018 to 0.256 ± 0.037 (p=0.93).ConclusionsDespite the increase between 2015 and 2016, the impact of the atraumatic lumbar puncture needle campaign has been marginal. Further efforts will be needed to effect a change in the ‘needle culture’ across neuroscience centres. Aside from the campaigning to highlight reduced complications and the cost-effectiveness of atraumatic needles, further initiatives such as a Delphi process should be considered.gideonadegboyega@gmail.com117

BackgroundOcrelizumab Phase III study safety findings in relapsing (OPERA I/II [NCT01247324/NCT01412333]) and primary progressive multiple sclerosis (ORATORIO [NCT01194570]) were reported; infections and serious infections are reported here. Methods: Ocrelizumab patients received 600 mg intravenously every 24 weeks for 96 weeks (OPERA I/II) or ≥120 weeks (ORATORIO; 2 × 300 mg infusions 14 days apart every 24 weeks). Controls received interferon beta-1a 44 µg thrice weekly (IFNβ−1a; OPERA I/II) or placebo (ORATORIO). Infections were classified by MedDRA system organ class/preferred term.ResultsNon-serious infection rates in ocrelizumab-treated patients in OPERA were 58.4% (pooled analysis) and ORATORIO 69.8%; comparators were IFNβ−1a 52.4% and placebo 67.8%. Most infections were mild-to-moderate. Common infections (≥10% in either group) reported more in ocrelizumab treated patients were upper respiratory tract infections and either nasopharyngitis (OPERA) or influenza (ORATORIO);<1% of ocrelizumab-treated patients withdrew due to non-serious infections. Serious infections occurred in 1.3% (OPERA) and 6.2% (ORATORIO) of ocrelizumab-treated patients; comparators were IFNβ−1a 2.9% and placebo 5.9%. No infection-related deaths occurred in ocrelizumabtreated patients in OPERA; two deaths occurred in ORATORIO (aspiration pneumonia and pneumonia [unrelated per investigator, related per sponsor]). No opportunistic infections were reported.ConclusionSerious infection rates with ocrelizumab were numerically lower than with IFNβ−1a and similar compared with placebo.

BackgroundCladribine tablets 3.5 mg/kg (CT3.5) demonstrated efficacy in RMS patients in CLARITY/CLARITY-Extension. Lymphopenia was common (CT3.5: mechanism of action).ObjectiveEvaluate whether lymphopenia persists following treatment/re-treatment with CT3.5 in CLARITY/CLARITY- Extension.MethodsLymphopenia by grade for patients randomised to CT3.5 throughout CLARITY/CLARITY-Extension (7 mg/kg cumulative 4 year dose; n=186) are reported. Patients with Grade 0 (G0) lymphopenia (≥1.0 × 109 cells/L) before the first course of CT and G0/1 (≥0.8 × 109 cells/L) before subsequent treatment in Years 2 (Y2), 3 and 4 were analysed.Results176 patients were G0 at the start of CLARITY (167 were G0/1; CLARITY-Extension). G3 lymphopenia was observed in 1% patients (Week-13, Y1), and in 7%, 11% and 12% patients at Week-12 in Y2, 3 and 4. In each year, G3 lymphopenia was observed in 1%, 4%, 4% and 4% patients (Week-24), in 1%, 2%, 2% and 2% patients (Week-36), and in 1% patients (Week-48) in Y2 only. G3 lymphopenia was reported in <18% patients at any time-point. No patients had G4 lymphopenia at the end of each treatment year.ConclusionsIn patients meeting treatment/re-treatment guidelines, no G4 lymphopenia occurred at the end of any treatment year; G3 lymphopenia was uncommon. Lymphocyte-based re-treatment criteria minimised the incidence of severe, sustained lymphopenia during 4 years’ treatment with CT.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_Year1-4.pdf

BackgroundPatients with high disease activity (HDA) relapsing-remitting MS are less likely to attain no evidence of disease activity (NEDA; no relapses, MRI activity or progression).ObjectivePost-hocanalysis to compare the proportion of patients with NEDA with cladribine tablets 3.5 mg/kg (CT3.5) vs placebo.MethodsPatients from CLARITY were retrospectively stratified using 2 definitions of HDA based on relapse history, prior treatment, and MRI characteristics: HRA (n=261) and HRA plus disease activity on treatment (HRA+DAT) [n=289]). Data for patients treated with CT3.5 or placebo who fulfilled these criteria and achieved NEDA status were compared over the 2 years using odds ratios (OR) and 95% CI.ResultsHRA subgroup: 76% of CT3.5-treated patients were relapse-free and 84% were T1 Gd+ lesion free vs 49% and 31%, respectively, for placebo. HRA+DAT subgroup: 77% of CT3.5-treated were relapse-free and 85% were T1 Gd+ lesion free vs 50% and 32%, respectively, for placebo. In the HRA and HRA+DAT subgroups, 43.2% and 43.7%, respectively, of CT3.5-treated patients were disease activity free compared with 8.7%, (OR: 8.02; 95% CI: 3.93 to 16.35; p<0.0001) and 9.0% (OR: 7.82; 95% CI: 4.03 to 15.19; p<0.0001) respectively, for placebo. In the overall population, composite NEDA score favored CT over placebo (OR: 4.46; 95% CI: 3.18 to 6.26; p<0.0001).ConclusionsTreatment with CT3.5 significantly increased the proportion of HDA patients with NEDA vs placebo.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_NEDA.pdf

IntroductionPatients with relapsing MS (RMS) who show an increased rate of relapse or disability worsening can be described as showing high disease activity (HDA). Treatment with cladribine tablets (CT) in the CLARITY study, and with CT added to interferon-β in the ONWARD study demonstrated efficacy vs. placebo (PBO) across a range of patients with active MS. Combining double-blind data from these studies allows assessment of the efficacy of treatment with CT 3.5 mg/kg (CT3.5; cumulative dose). The objective of this post-hocanalysis is to compare the effects of CT3.5 vs. PBO on the proportion of patients achieving no evidence of disease activity (NEDA) status in HDA subgroups identified using two sets of criteria in a pooled cohort of patients from CLARITY and ONWARD.MethodsPatients from CLARITY and ONWARD were retrospectively stratified using 2 sets of HDA criteria based on relapse history, prior treatment, and MRI characteristics: high relapse activity (HRA; n=314) and HRA plus disease-activity-on-treatment (HRA +DAT; n=459). Patients treated with CT3.5 or PBO who fulfilled these criteria and achieved NEDA were compared over 2 years using odds ratios (ORs) and 95%CIs.ResultsIn the HRA subgroup, 76.5% of CT3.5-treated patients were relapse-free, 86.7% were T1 Gd +lesion free vs. 50.7% and 35.8%, respectively, for PBO. In the HRA +DAT subgroup, 77.6% were relapse-free and 88.8% were T1 Gd +lesion free with CT3.5 vs. 53.9% and 40.8%, respectively for PBO. In the HRA and HRA +DAT subgroups, 42.7% and 41.3%, respectively, of CT3.5-treated patients were disease activity free compared with 9.7%, (OR 6.94, 95% CI 3.67;13.12, p<0.0001) and 13.7% (OR 4.28, 95% CI 2.62;6.99, p<0.0001) respectively, of PBO recipients. In the overall CLARITY+ONWARD population (including non-HDA patients), the composite NEDA score also favoured CT over PBO (OR 3.95, 95% CI 2.90;5.37, p<0.0001).ConclusionCompared with placebo, treatment with CT3.5 was associated with increased odds of achieving NEDA in HDA patients.

BackgroundAlemtuzumab is an effective disease modifying treatment (DMT) for people with relapsing multiple sclerosis (pwRMS). Its mechanism of action includes profound lymphocyte depletion.ObjectiveTo analyse the pattern of lymphocyte depletion and associated infections after alemtuzumab administration in a cohort of pwRMS treated at our centre.MethodspwRMS treated with alemtuzumab were identified on our clinical record system (Cerner Millennium). Baseline blood results, total lymphocyte counts (TLC) and infections post-treatment were studied.Results84 pwMS on alemtuzumab were followed up for a mean of 8.7 months. One month after the first treatment cycle, TLC was 13% of baseline (from 2.2 to 0.28 × 109/l). TLC recovered to >0.6 by month 3 and to >1 by month 9, however remained below baseline in all pwRMS. After the 2nd treatment cycle, TLC reconstitution was more rapid, to >1×109/l within six months. 19 (23%) pwRMS had infections within four months of treatment cycles. Infections affected the respiratory tract in 7 (8%) pwRMS, and the urinary tract in 9 (11%). All but one infection occurred with TLC <0.6.ConclusionInfections are common in pwRMS treated with alemtuzumab. To reduce their incidence prophylactic antibiotics should be considered in pwRMS with TLC of <0.6×109/l.

BackgroundIn the CLARITY study, treatment with cladribine tablets (CT) vs placebo showed strong efficacy in patients with RMS. Post-hoc analysis may provide insights into the efficacy of CT in patients with HDA.ObjectiveTo compare the effects of CT 3.5 mg/kg (CT3.5) vs placebo using two HDA definitions.MethodsPatients randomised to CT3.5 (n=433) or placebo (n=437) were analysed using two HDA definitions based on high relapse activity ([HRA]≥2 relapses in the previous year) regardless of prior treatment, or a HRA plus treatment nonresponse ([HRA +TNR]≥2 relapses in the previous year, or ≥1 relapse in previous year while on DMD therapy and ≥1 T1 Gd +or ≥9 T2 lesions).ResultsIn the overall population, CT3.5 reduced risk of 6 month EDSS progression by 47% (HR=0.53,95%CI:0.36;0.79) vs placebo. A larger risk reduction for CT3.5 vs placebo of 82% was seen in the HRA and HRA +TNR subgroups (HR=0.18 each,95%CI:0.08;0.44 and 0.07;0.43). ARR was lower with CT3.5 than placebo in the overall population (RR=0.42,95%CI:0.33;0.52), and even lower for HRA (RR=0.32,95%CI:0.22;0.47) and HRA +TNR (RR=0.33;95% CI:0.23;0.48).ConclusionsPatients identified by HDA criteria showed clinical and MRI responses to CT3.5 that were generally better than, or at least comparable with, outcomes in the overall CLARITY population.

BackgroundEvidence suggests cladribine is an effective, safe and convenient disease modifying therapy (DMT) for people with multiple sclerosis (pwMS).ObjectiveTo report our clinical experience using cladribine in pwMS using a dosing scheme adapted to individual total lymphocyte count (TLC) thereby addressing a key safety concern raised in the rejection of oral cladribine by the European Medicines Agency in 2011.MethodsSubcutaneous cladribine 10 mg/day was administered on up to seven days in five weeks to pwMS who had clinical and/or MRI disease activity. The number of injections was adjusted to individual TLC to avoid depletion below 0.5 × 10* 9/L (WHO Grade 3 or 4). Efficacy and safety were assessed.ResultsForty-nine pwMS (31 women and 18 men, aged 44 years (SD=9 )) were followed up for a mean of 6 months after their first cladribine injection. Median EDSS at baseline was 5 (1–8, n=46). No serious treatment-related adverse event was observed, and neither any clinical disease activity. TLC dropped to between 0.5 and 1 × 10* 9/L while other white cells remained within normal range.ConclusionCladribine was well tolerated and led to controlled TLC depletion leaving other cell lines largely unaffected. So far no new disease activity has been detected. Follow-up continues.

BackgroundOcrelizumab significantly reduced the risk of confirmed disability progression (CDP) versus placebo in the Phase III ORATORIO study (NCT01194570) in primary progressive multiple sclerosis (PPMS). A composite measure of CDP (cCDP) that also includes upper extremity function and ambulation speed may address limitations in using the Expanded Disability Status Scale to define CDP.ObjectiveTo assess the effect of ocrelizumab on 12- and 24 week cCDP in patients with PPMS.MethodsPatients received ocrelizumab (n=488) 600 mg (administered as two 300 mg infusions 14 days apart) or matching placebo (n=244) every 24 weeks for ≥120 weeks, and were assessed for cCDP (ie, time to first onset of either CDP,≥20% worsening on the timed 25-foot walk [T25FW] test or ≥20% worsening on the 9-hole peg test [9HPT]), sustained for ≥12 or≥24 weeks.ResultsOcrelizumab reduced the risk of 12- and 24 week cCDP versus placebo by 26% (HR: 074; p=0.0014) and 29% (HR: 0.71; p=0.0008), respectively. Ocrelizumab also significantly reduced the risk of individual cCDP components versus placebo, including 12- and 24 week CDP and confirmed ≥20% worsening on T25FW and 9HPT.ConclusionsOcrelizumab showed consistent benefit on disability progression, ambulation and upper limb function assessed using cCDP in patients with PPMS.