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The failure of relapses and white matter lesions to properly explain long-term disability and progression in multiple sclerosis is compounded by its artificial separation into relapsing remitting, secondary progressive, and primary progressive pigeonholes. The well-known epidemiological disconnection between relapses and long-term disability progression has been rediscovered as “progression independent of relapse activity”, i.e. smouldering multiple sclerosis. This smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI. We recognise that smouldering associated worsening and relapse/lesion associated worsening coexist, to varying extents.

Introduction:Cognitive impairment in multiple sclerosis (MS) is increasingly being investigated with resting-state functional MRI (rs-fMRI) functional connectivity (FC). However, results remain difficult to interpret, showing both high and low FC associated with cognitive impairment. We conducted a systematic review of rs-fMRI studies in MS to understand whether the direction of FC change relates to cognitive dysfunction, and how this may be influenced by the choice of methodology.Methods:Embase, Medline, and PsycINFO were searched for studies assessing cognitive function and rs-fMRI FC in adults with MS.Results:Fifty-seven studies were included in a narrative synthesis. Of these, 50 found an association between cognitive impairment and FC abnormalities. Worse cognition was linked to high FC in 18 studies, and to low FC in 17 studies. Nine studies found patterns of both high and low FC related to poor cognitive performance, in different regions or for different magnetic resonance (MR) metrics. There was no clear link to increased FC during the early stages of MS and reduced FC in later stages, as predicted by common models of MS pathology. Throughout, we found substantial heterogeneity in study methodology, and carefully consider how this may impact on the observed findings.Discussion:These results indicate an urgent need for greater standardization in the field—in terms of the choice of MRI analysis and the definition of cognitive impairment. This will allow us to use rs-fMRI FC as a biomarker in future clinical studies, and as a tool to understand mechanisms underpinning cognitive symptoms in MS.

•In 5633 participants, the prevalence of depression in Multiple Sclerosis was 25.3%.•29.9% of depressed people with Multiple Sclerosis were untreated for depression.•Of those treated, 26.1% still had a symptom level consistent with a probable case.•Depression was increased by comorbidities, anxiety, fatigue, smoking and disability.•Depression trajectories fall into 3 groups with differing clinical needs.

•The Rasched Multiple Sclerosis Vision Questionnaire-7 is precise and interval-level.•Visual problems are very common in Multiple Sclerosis, reported by 80% (n = 5478).•Smaller changes in visual symptoms matter more to relapsing than progressive patients.•Visual problems increase depression risk after discounting age, gender and disability.

•This comprehensive scoping review benchmarks the international evidence base for access to health and social care for MS patients.•There are inequalities across the prevention, care and support pathway, particularly for men, older age groups, lower SES, and those with MH problems.•There are clear implications for clinicians, health organisations and national policies.•There are specific research gaps particularly for vulnerable groups and for patient information.•These findings will help to inform prioritisation of future research internationally for this population.

•MS professional interviews reveal factors underlying variation in DMT prescribing.•Neurologists differ in perceived restrictiveness of prescribing guidelines.•Eligibility criteria are seen as open to interpretation leading to individual bias.•Readiness to prescribe DMTs is related to risk-benefit beliefs and drug familiarity.•Prescribing is influenced by national peer networks and local prescribing cultures.

•This long-term study examined the effects of natalizumab treatment at 5.5 years.•Disability worsening events confirmed at 24 weeks may not be sustained at 48 weeks.•Relapses contribute significantly to EDSS worsening.

No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5modulator, on disability progression in patients with SPMS.

•Administration- and monitoring HCP time was measured for some high-efficacy DMTs•A model was built using observational study results and data from HCP interviews•Infused DMTs were projected to require the greatest amount of HCP time over 4 years•Oral high-efficacy DMTs were projected to require the lowest HCP time over 4 years•Findings may assist planning and delivery of equitable provision of DMT services

•Ethnicity impacts the incidence and prevalence of MS.•People with MS of Black and Hispanic ethnicities appear to have a greater severity of radiological disease activities compared to those of a White ethnicity.•People with MS of Black, Hispanic, and Middle Eastern and North African ethnicities, but not other Asian ethnicities accumulate disability faster than those of a White ethnicity.•Interferon-beta may be less efficacious in people with MS from Black ethnicity.

•Clinical trial populations do not fully reflect routine practice. The power of routinely collected data to inform clinical practice is increasingly recognised.•The OPTIMISE:MS pharmacovigilance study is a prospective, pragmatic observational study, conducted across 13 UK MS centres.•342 clinical events were reported during follow up of 2112 participants•We demonstrate how routinely collected healthcare data can be used to evaluate the safety of DMT for people with MS, and that it is possible to distinguish drug-related and disease-activity related risks.

DMF a montré un profil bénéfice–risque favorable dans les essais et en pharmacovigilance. DMF est recommandé chez les femmes enceintes que si le bénéfice justifie le risque pour le fœtus.

We present the case of a 54 year old woman with known relapsing-remitting multiple sclerosis who presented with acute respiratory deterioration five weeks after a first course of alemtuzumab. Imaging showed bilateral ground glass changes and extensive investigations confirmed chest infection with dual pathogens - Pneumocystis jirovecii and Cytomegalovirus. She responded to standard anti-PJP and CMV therapy and was discharged on oral prophylaxis. Opportunistic infections in the weeks immediately following alemtuzumab therapy remain an uncommon complication but one that requires clinical vigilance, careful monitoring and appropriate prophylactic therapy.

•MS patients experienced fear, loss of control and hopelessness at diagnosis.•Choosing disease modifying treatments was accompanied by fear and uncertainty.•Treatment decisions gave opportunity to increase hope, control, and acceptance.•Treatment choices were motivated by a desire for normality.•Patients were concerned about future employment and family planning.

IntroductionThis audit (presented ABN2021), identified multiple problems highlighting that the UK MS community should maximise influence, efficiency and data usage. Here, we address how.AimTo present practical steps taken to improve UK MS care.MethodsAudit results were discussed with key stakeholders. Potential projects were proposed, discussed and refined. A set of deliverable projects actionable by the UK MS community was identified.Funding models that maximise investments were considered. ResultsThe projects, for which funding has been sought, are:• Clarifying roles and responsibilities of MS team members• Website, to facilitate communication and good practice repository• Where’s the care? – UK MS care map development• Recording care – MS team documentation• Measuring outcomes – MS expectation frameworks (for Patients and teams)• Maximising core activities – making blueteq (and prescribing databases) indispensable• Advancing data value – improving Hospital Episode Statitics• (HES data) For delivery, quality and routine use• Ensuring the future – making MS an attractive career optionFor delivery, a ring-fenced entity (Transforming MS 4 All) was established within an existing not-for-profit community interest company (CiC).ConclusionsThese deliverable, impactful projects should improve UK MS care. Managing finances under a CiC enables transparency, accountability and reinvestment of funding, to sustain services. Neverthe- less, much more is needed.

IntroductionDimethyl fumarate (DMF) is not recommended during pregnancy and should only be used if the potential benefit justifies potential foetal risk. Given limited pregnancy data, the UK and Ireland have enrolled DMF-exposed pregnant women in an ongoing international registry assessing pregnancy outcomes. In the general population, 62% of pregnancies end in live birth, 22% in abortion, and 16% in foetal loss, with similar rates in multiple sclerosis (MS) patients.MethodsWomen with MS exposed to DMF since the first day of their last menstrual period before con- ception/during pregnancy were included. UK/Ireland Coordinating Centres liaised directly with patients and healthcare providers.ResultsAs of March 2021, 403 patients (19 UK/Ireland) were enrolled. Of 350 reported pregnancy outcomes (19 UK/Ireland), 329 (94%) represented live births (100% UK/Ireland). Of 326 infants with known gestational age,298 births (91%) were full-term (100% UK/Ireland) and 28 (9%) premature (<37 weeks). Of the 21 (6%) cases of foetal loss, 19 were spontaneous abortions (1 each ectopic and molar pregnancy) and 2 foetal deaths (>28 weeks). There was one neonatal death. Nine infants (2 UK/Ireland) had EUROCAT-confirmed birth defects.ConclusionsThe observations are consistent with MS and general populations.SupportBiogen. Disclosures on poster.

BackgroundWe present baseline data on the first 50 participants recruited to the UK MS Pregnancy Register.MethodsData collected via questionnaires from consenting participants until 20th December 2021 were included.Results50 participants (all with relapsing remitting MS; mean age at diagnosis 28.0 years; mean age at recruitment 33.0 years) were included. Median EDSS was 2.5 (n=16). Gestation at recruitment ranged from 2 to 40 weeks. 78% had discussed their pregnancy in advance with their MS team. 90% of patients had ever taken DMT. Of the patients that stopped DMT (n=23), 16 reported stopping for pregnancy-related reasons. Of these, 39% stopped before pregnancy and 30% following conception. 15 women are continuing DMT during their current pregnancy, taking the following DMT: Glatiramer acetate (n=5), natalizumab (n=7), Peginterferon beta-1a (n=2), not recorded (n=1). In those with prior pregnancies, 61% (14/23) reported pregnancy loss with 1 case of a rare genetic condition in the baby. None of the prior pregnancy losses happened whilst on DMT. One participant reported previous PPH and foetal macrosomia and another reported previous pre-eclampsia.ConclusionsThese results show that a patient-facing pregnancy MS registry is feasible and can collect previous adverse pregnancy outcomes. Future results will inform clinicians and women about the safety of DMT and adjunctive medication during pregnancy and postpartum.

BackgroundTo assist neurologists with effectively planning multiple sclerosis (MS) services in the NHS, this study quantified the administration and monitoring time burden associated with selected high-efficacy disease-modifying therapies (DMTs; alemtuzumab, cladribine tablets [CladT], fingolimod, natalizumab, and ocrelizumab) for highly-active relapsing MS in the UK.MethodsA time and motion study was conducted across four MS centres over 3–4 months per-site (Aug 2019–Feb 2021). Time dedicated by healthcare professionals (HCPs) to pre-specified drug administration and monitoring activities was assessed for each of the selected DMTs. Data were extrapolated over 4 years per-patient, based on the relevant Summaries of Product Characteristics, and analysed descriptively.ResultsFor oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 12.3 hours for CladT and 15.9 hours for fingolimod. For infusion DMTs, total time (administration and monitoring) was 35.5 hours for alemtuzumab (6.1 and 29.4 hours), 46.5 hours for natalizumab (17.2 and 29.3 hours), and 21.6 hours for ocrelizumab (6.2 and 15.4 hours).ConclusionsWhile active HCP time varies across sites, infusion DMTs are projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs.

BackgroundNatalizumab has been used for treatment of rapidly evolving sever relapsing remitting multiple sclerosis (MS) and is associated with risk of progressive multifocal leukoencephalopathy (PML). Patients can switch treatment after two years if JCV antibody-index is positive. One of the alternative treatment options include a weight based adjusted cladribine tablets that have been approved for treatment of highly active relapsing-remitting MS in Europe since 2017.MethodsWe reviewed 20 patients with prior natalizumab-treatment that switched to oral cladribine. The objective for treatment modification was JCV-index positivity. Data was collected regarding MS relapses, disease progression, or any possible adverse events.ResultsPatients started cladribine treatment between 01/2018 and 07/2019 with a follow-up observation period from 3 weeks to 18 months. Treatment was well tolerated and there were no severe opportunistic infections.ConclusionAccording to this review of 20 patients, treatment with cladribine tablets was safe even when used in patients previously treated with natalizumab and at high risk for PML. So far, no serious adverse events other than transient lymphopenia have been observed, especially no cases of PML.j.das@doctors.org.uk

BackgroundThere is limited evidence to guide DMT prescribing prior to and during pregnancy, leading to wide variation in practice. In 2019, ABN consensus guidelines were published to address this. We set out to establish what impact these have had.MethodsAn online questionnaire was cascaded to UK MS neurologists. Individuals completed the ques- tionnaire anonymously.Results85 responses were obtained; 76 from DMT prescribers in a variety of settings. 74/76 (97%) were aware of the ABN guidelines. 74% reported a recent change in prescribing IFN-B and 70% in prescribing natalizumab around pregnancy, compared to 5% for alemtuzumab and 1% for teriflunomide and fingoli- mod. The ABN guidelines were the most commonly cited reason for change (58 individuals), followed by SmPC changes and influence from peers.There was significant variation in natalizumab prescribing - 51% ‘normally continue to prescribe’ until 34/40, 12% stop when pregnancy confirmed and 11% stop prior to conception. 58% encourage breastfeeding on natalizumab whilst 34% discourage this.ConclusionsThere remains significant variation in advice given to women with MS considering pregnancy. This is most marked with higher efficacy DMT, where risk-benefit decision making is complex. Additional data and resources for women with MS, including a UK MS Pregnancy register, are urgently needed.ruth.dobson@qmul.ac.uk

IntroductionDimethyl fumarate (DMF) is not recommended for use during pregnancy and should only be used if the potential benefit justifies the potential foetal risk. Given limited pregnancy data, the UK and Ireland have enrolled DMF-exposed pregnant women in an ongoing international registry assessing pregnancy outcomes. Generally, pregnancies end in live birth (62%), abortion (22%), or foetal loss (16%), with similar rates in MS patients.MethodsPregnant women with MS exposed to DMF since the first day of their last menstrual period before conception/during pregnancy were included. UK/Ireland Coordinating Centres liaise directly with patients and healthcare providers.ResultsAs of May 2020, 345 patients (18 UK/Ireland) were enrolled. Of the reported 351 pregnancy outcomes (18 UK/Ireland), 277 (79%) represented live births (17 UK/Ireland) and 74 (21%) foetal loss. Of infants with known gestational age (n=274), 249 births (91%) were full-term (17 UK/Ireland) and 25 (9%) premature (<37 weeks). There were 17 spontaneous abortions (1 each ectopic and molar pregnancy) and 1 foetal death (at >28 weeks). No infant or maternal deaths were reported. Ten infants (4%) (2 UK/Ireland) had confirmed birth defects.ConclusionsObserved safety signals were consistent with MS and general populations.SupportBiogen. Disclosures: Included on poster 81david.rog@srft.nhs.uk

IntroductionThe UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address caseloads managed and use of databases.AimTo document the workload of MS Teams and how they record their patients.MethodsWe asked all MS services to complete service questionnaires, supplemented with individual clinician interviews. Specifically, we asked about total caseload, DMT caseload, annual service expansion, accuracy of their estimates and use of databases.Results70 MS centres care for 105522 people with MS, 85% of the estimated UK MS population.Estimates were large and variable for total caseloads (median caseload/service=1300 patients, range 96–5500, SD=1247) and DMT caseloads (median = 545 patients, range 79–2300, SD 577). Estimated annual service expansion varied between 5%-14%. Only 20% of participants graded these estimates as “very accurate”. 98% of participants used an MS patient database. However, many questioned their validity. Few used a prospectively updated database facilitating clinical practice. The vast majority used Excel- based patient-lists, mostly people on DMTs, for safety monitoring.ConclusionsEnhanced digital maturity and linked data sources will facilitate patient identification, clinical decision-making, service planning, management and outcomes. We recommend MS Teams are supported to advance along the continuum of digital maturity, from their current position, to prospec- tively maintained accurate lists of all MS patients, through routine visualisation and analysis of longitudinal minimum datasets, to networked clinical management systems.Acknowledgements.Neurology Academy david.rog@srft.nhs.uk

IntroductionThe UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address MS-specific Multidisciplinary Team (MS-MDT) meetings, an NHSE requirement for services prescribing disease modifying treatments (DMTs), although the wider MS-MDT parameters are less clear.AimTo document the characteristics and variability in UK MS-MDTs.MethodsWe asked all MS services to complete service questionnaires, supplemented with individual clinician interviews. Specifically, we asked about occurrence, frequency, who attends, and numbers and types of patients discussed at, MS-MDTs.ResultsForty-six of the 70 centres (68%) had an MS-MDT, 63% were weekly. Neuroradiologists attended only 49%, MS Coordinators 79% and Neuropharmacists 50%, of meetings. Neurology SpRs (73%) and Research Registrars (62%), attended the majority of MS-MDTs. A mean of 9 patients (range 1–40, SD 7) were discussed, predominantly complex patients and/or those considered for high efficacy DMTs.ConclusionsThere was considerable variation in the occurrence, frequency, composition and types of patients discussed at UK MS MDTs. Neuroradiologists absence is concerning, given the central role of MRI in MS clinical decision-making. Neuropharmacists and MS coordinators absence, limits the wider benefits from MS Team members. The MS-MDT is a regular touch point and a significant educational opportunity for the whole team, including trainees. We recommend that the UK MS community defines the param- eters of an MS-MDT so that these can be consistently implemented, through job-planning, across services.davidrog@srft.nhs.uk80

IntroductionThe UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address MS Team staffing and their levels of coping.AimTo document the observed MS Teams staffing levels, ascertain their proposed staffing requirements and determine the extent to which they feel are coping with their workload.MethodsMS services completed service questionnaires, supplemented with individual clinician interviews. Specifically, we asked about MS Team composition and contribution to MS care, estimated sustainable caseloads per MS neurologist and coordinator, referencing the MS Trust’s recommendations for nurses. Finally, participants graded the degree to which their service was coping.ResultsMS Team structures varied. MS coordinators (44%) or neuropharmacists (40%) were uncommon and the ratio of prescribing neurologists to ms nurses varied (4:1 to 1:4). Based on respondent’s subjective estimatesa,b and empirical evidencec for sustainable caseloads, implied per centre staffing shortfalls of:1.8 MS neurologistsa, 2.4 MS nursesc, 2.6 MS coordinators b. No centre felt that they were “coping very well”, 42% were “struggling to cope”. Neither caseloads, nor staffing numbers, per se, predict levels of coping.ConclusionsStaffing shortfalls and perceived lack of coping imply the value of: strategic delivery of networked-services, formalising MS team structures and staffing ratios, role and responsibilities, and the need to work differently.Acknowledgements.Neurology Academy david.rog@srft.nhs.uk

IntroductionThe UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address MS disease modifying treatment (DMT) prescribing.AimTo document MS Teams’ DMT prescribing.MethodsWe asked all MS services to share their MS DMT prescribing for the 2018/2019 financial year. We computed: the proportion of people living with MS (PLwMS) on DMTs; drugs prescribed, ratios of higher- to-lower potency drugs, costs to the NHS.ResultsTo date, 49/70 (70%) services have shared data (none declined our request). They treated >21,000 people with DMTs. The proportion of PLwMS on DMTs varied 5.5-fold (range=14.6% to 79.4%; mean=39%).Most services (34/49; 69%) had unrestricted prescribing. These services varied 5-fold (9% to 50%) in the proportion of people prescribed monoclonal antibodies (alemtuzumab, natalizumab, ocrelizumab).The total annual spend from 49 services exceeded £261 million (extrapolated to £373million from 70 services). Mean DMT spend/patient was £12,096 but varied 3.6-fold (£7,116 to £25,833).NHSE quote the total annual increase in DMT spend was 10% in 2019/2020.ConclusionsDMT prescribing variations are expected, but important, if associated with differing outcomes. We recommend the substantial DMT spend and its increase, demands UK investment to: maximise processes (full data reporting to prescribers) and outcome measurement (including dashboard of longi- tudinal and peer-benchmark prescribing practice, eg induction vs escalation approaches and sequenc- ing) to provide optimal real world evidence to guide prescribing.AcknowledgementsNeurology Academy david.rog@srft.nhs.uk79

IntroductionWhilst GIRFT highlights long-recognised variations in MS service provision and disease modifying treatments (DMTs) prescribing, sources of variations weren’t explored.AimThe UK MS Service and Prescribing Audit was undertaken to better understand MS care, contextualise sources of variation and facilitate service development.MethodsWe asked all MS services to complete service questionnaires, supplemented with individ- ual clinician interviews covering; caseload, databases, staffing, neuroradiology, MDT, coping. We also requested anonymised blueteq or internal DMT prescribing data for 12 months to 31st March 2019.Results70 MS services participated. They care for >105,522 people with MS, ≈85% of the estimated UK MS population. To date, 49 MS services have provided DMT prescribing data for over 21,000 patients, a combined spend of over £261 million in the financial year to March 31st 2019. Consistent findings, detailed in five other abstracts, include: high caseloads, inconsistent team structures, low staffing levels, limited data collection and usage and access to support services.ConclusionsThis audit illustrates significant engagement from the UK MS community, with a representa- tive sample, providing a real opportunity to effect change. We recommend working across the UK MS network with multiple stakeholders to (1) maximise influence for change, (2) develop new ways of working to deal with workload, including enhancing data maturity and optimise team structures, and (3) build MS team resilience and sustainability.Acknowledgement.Neurology Academy david.rog@srft.nhs.uk

IntroductionGIRFT utilises comparator data to assess variation in practice, including HES data. Context and accuracy underpin meaningful data analysis. Dashboards enable similar components of service delivery to be compared and benchmarked.MethodsDR, JH and JM, worked with JC, to develop a bespoke MS HES dashboard, utilising IQVIA’s HES dataset (from 2014), in Tableau, for people with MS accessing hospital care in England. Multiple filters relevant to clinical practice were created.ResultsConsistent MS-related activities were very inconsistently reported across Trusts. Some Trusts report infusion-related activities as elective day cases, others as elective inpatients, some report as both. For the 2019/2020 financial year, the MS variances listed below were compared for 4 Trusts (Barts Health, Univer- sity Hospitals Birmingham, University Hospital Plymouth, Salford Royal). Elective waiting list: 42%, 57%, 9%, 8%; Elective planned admissions: 38%, 3%, 5%, 74%; Elective Booked admissions: 0%, 6%, 52%, 3%. These probably represent systematic differences in reporting admission methods, rather than significant differ- ences in types of admissions, but clarification is required.ConclusionTrusts report the same activity differently in HES. We recommend enabling MS services to examine, critique and benchmark their clinical practice routinely. Cautious interpretation of MS outcome comparisons is required until data are consistently reported. Acknowledgement Roche Products Ltd provided funding but had no control over dashboard content, maintenance or distribution.davidrog@srft.nhs.uk78

IntroductionThe UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address access to Neuroradiology and Neuroradiologists.AimTo document the variability in access to Neuroradiology support, for UK MS Teams.MethodsWe asked all MS services to complete service questionnaires, supplemented with individual clinician interviews. Specifically, we asked about access to specialist Neuroradiologists, timeliness, out- sourcing and quality of MRI reporting and impact upon care.Results70 MS centres contributed MS service data, encompassing over 105522 people with MS, ≈85% of the UK MS population.76% of respondents felt at least half of MRI scans were reported in a timely manner, however 46% felt lack of access to MRI impacted upon the care they could offer. 68% of centres had scans reported by a neuroradiologist, however 63% of centres outsourced reporting and 69% of centres were concerned about reporting quality and the necessity for re-reporting.ConclusionsSignificant variability exists in the reporting of MS scans in the UK. This could impact upon access to, and use of, DMTs in centres and is increasingly important, given the availability of high efficacy DMTs, their sequencing and their potential adverse events.We recommend partnership working between MS Teams and Neuroradiologists to maximise dissemina- tion of expertise and minimise inefficiency in access to, reporting and discussion of, MS scans, at local, regional network and national levels.david.rog@srft.nhs.uk

IntroductionThe delayed-release dimethyl fumarate (DMF) label recommends use during pregnancy only if potential benefit justifies the potential risk. Given limited pregnancy data, United Kingdom (UK) and Ireland are enrolling DMF-exposed pregnant women into an ongoing international registry assessing pregnancy outcomes. Pregnancies end in live birth (62%), abortion (22%), and fetal loss (16%) in general, with similar rates in MS patients.MethodsPregnant women with MS exposed to DMF since the first day of their last menstrual period prior to conception/during pregnancy were included. The UK/Ireland Coordinating Centres liaise directly with patients and HCPs.ResultsAs of April 2019, 263 patients (14 patients from UK/Ireland) were enrolled. Of the 214 pregnancy outcomes (12 UK/Ireland) reported to date, 197(92%) were live births (12 UK/Ireland) and 17(8%) foetal loss. Of infants with known gestational age (n=197), 176(89%) births were full-term (12 UK/Ireland) and 18(9%) premature (<37 weeks). There were 16 spontaneous abortions (1 ectopic pregnancy), and 1 foetal death at ≥28 weeks of gestation. No molar pregnancies or infant or maternal deaths were reported. Seven(4%) infants (1 UK/Ireland) had confirmed birth defects.ConclusionNo safety signal was observed, consistent with MS and general populations. Support: Biogen; disclosures detailed on poster.david.rog@srft.nhs.uk

•Deprivation negatively affects the access to DMTs for MS.•Living in more deprived areas reduced the likelihood of receiving DMTs for MS.•Barriers to housing and services contributed to this disparity in accessing DMTs.•Overall, effects of deprivation were small in a publicly funded healthcare system.

Introduction:Although the Cannabis sativaherb has been known for its therapeutic benefit for centuries, the interest in the clinical potential of cannabinoid-based drugs escalated after the discovery of the endocannabinoid system. The understanding of their actions at the molecular level indicates that the therapeutic applications of cannabinoids (plant-derived or synthetic) may be diverse. Several drugs containing cannabinoids are currently used in the therapy of emesis, pain and spasticity.Areas covered:This drug discovery case history reviews the preclinical and clinical development of Sativex (‘‘delta-9-tetrahydrocannabinol, cannabidiol’’; nabiximols). Sativex is the first licensed phytocannabinoid-based drug approved, or in the process of approval, as therapy for indications such as MS-associated spasticity or chronic pain. Sativex contains a combination of two cannabinoids in approximately equal quantities (δδ-9-tetrahydrocannabinol and cannabidiol) and is administered via an oromucosal pump spray, aiming at minimising psychotropic side effects and first pass effect. Pivotal clinical safety and efficacy data that led to Sativex's approval are discussed, as well as issues that have arisen with its clinical usage.Expert opinion:Although pleiotrophic effects of cannabinoids may raise complex issues beyond their symptomatic effects, standardised pharmaceutical cannabinoids may constitute a useful addition to the pharmacotherapeutic armamentarium in chronic conditions insufficiently alleviated by existing drugs.

Fingolimod, a sphingosine‐1‐phosphate receptor modulator, is a novel oral treatment for multiple sclerosis. In this Drug profile the author reviews its mode of action, likely positioning and the advantages that it might offer in terms of clinical management of multiple sclerosis, and begins by setting the treatment context.

Le diméthyl fumarate (DMF) à libération prolongée ne devrait être utilisé lors de la grossesse que si le bénéfice potentiel l’emporte sur le risque éventuel pour le fœtus, conformément aux recommandations figurant sur son étiquette.

Central pain in multiple sclerosis (MS) is common and often refractory to treatment.

•COVID19 is associated with multiple sclerosis exacerbations.•Protecting people with multiple sclerosis against COVID19 is important.•Disease modifying therapies prevent new multiple sclerosis symptoms during COVID19.

•Across age groups, alemtuzumab efficacy was greater than SC IFNB-1a over 2 years.•Alemtuzumab maintained clinical and MRI efficacy over 8 years in all age groups.•Age-related increases in serious infections, malignancies, and deaths were observed.

BackgroundThere is a significant UK variation in the DMT sequencing strategies for high PML risk patients on Tysabri. In Greater Manchester Neuroscience centre we gradually reduced the number of high PML risk patients on Tysabri from 89 in 2016 to 26 in 2018. From our experiences de-escalation strategy from Tysabri to Fingolimod or Lemtrada seemed safe. Fingolimod, less efficacious switch, tends to be delivered quicker than Lemtrada (requiring lesser safety checks), but the efficacy of Lemtrada in MS patients with disease duration >10 years remains uncertain.MethodBetween January 2018 and November 2018 we switched 14 high risk PML patients from Tysabri to Mavenclad. All patients underwent MDT discussion, lumbar puncture with JCV PCR and MRI checks prior to DMT switch.ResultsWe present the first UK MS patient cohort de-escalating from Tysabri to Mavenclad. Older (average age of 44) and more disabled patients (average EDSS=4.75) opted for Mavenclad, with equal gender distribution (7:7). Average disease duration was 7.5 (2–10) and patients received 52 (6–107) Tysabri infusions. 5 patients had other DMTs prior to Tysabri (5 Copaxone, 1 Rebif, 1 Tecfidera), 9 patients had Tysabri as their first DMT. Average JC-virus serology titer was 1.86.ConclusionSwitching high PML risks patients from Tysabri to Mavenclad appears to be well tolerated; regular MRI monitoring showed no PML carry-over risk and no significant MS disease activity.

•Recent clinical relapse and routine monitoring are the most common indications for requesting an MRI scan in MS clinical practice.•In routine monitoring, the addition of spinal imaging to brain showed no significant difference in treatment decision at subsequent clinical review.•Approximately 1 in 5 gadolinium administered scans showed enhancement, and in 1 in 20 patients, gadolinium enhancement was the only evidence of radiological disease activity.•Mean inter-scan intervals in relapsing-remitting MS for routine monitoring was 19.2 months (SD 20.7) with wide variation between MS centres.•MRI protocols amongst MS centres demonstrated significant variation in the sequences used for diagnostic, monitoring and pharmacovigilance scans.

•Normal live birth was the most common pregnancy outcome after alemtuzumab treatment•Spontaneous abortion rates were comparable with the general population•Timing of alemtuzumab exposure had no impact on the risk of spontaneous abortion•Relapse rates in alemtuzumab-treated patients increased minimally postpartum

Available data from clinical trials and post-marketing reports show no safety signals with delayed-release dimethyl fumarate (DMF) exposure during pregnancy.

BackgroundAlemtuzumab, a CD52 - specific monoclonal antibody depletes T and B cell population to reduce relapse in multiple sclerosis. Neutrophils also express low levels of CD52 and can be depleted transiently by alemtuzumab, increasing the risk of infection in the post-alemtuzumab treatment period.AimIn this study in the Greater Manchester Neuroscience Centre (GMNC) we investigated at risk population for alemtuzumab induced neutropaenia. The outcome of these patients is also discussed.MethodRetrospective study of patients who developed neutropaenia following treatment with alemtuzumab at the GMNC. Data of patient demographics, grade of neutropeania, symptoms while neutropaenic and management were evaluated.ResultsOf the 131 patient (86 F: 45 M) treated with alemtuzumab (1.9 F: 1 M ratio), 18 patient (13.7%) developed neutropaenia (17 F Vs 1 M, 19.8% F Vs 2.2% M). Moderate to severe (grade 2–4) neutropaenia was only observed in females. Average duration to develop neutropaenia was 41 days. While neutropaenic 16 patients were asymptomatic, 1 developed flu-like illness and 1 had recurrent chest infection requiring antibiotic.ConclusionIn our experience, women are at significantly higher risk of alemtuzumab induced neutropaenia. Monthly serial blood monitoring is adequate for most patients and specific intervention rarely required.

IntroductionData regarding delayed-release dimethyl fumarate (DMF) use, an approved MS treatment, in pregnant women is limited. United Kingdom (UK) and Ireland are enrolling DMF-exposed pregnant women into TecGistry, an ongoing prospective, observational registry to assess pregnancy outcomes.MethodsPregnant women with MS exposed to DMF since the first day of their last menstrual period prior to conception or at any time during pregnancy were included. The UK and Ireland Coordinating Centres (Manchester Centre for Clinical Neurosciences and St. Vincent’s University Hospital, Dublin) liaise directly with DMF-exposed patients and their HCPs.ResultsAs of 24 April 2018, 220 patients (11 patients from UK/Ireland) were enrolled; 161 pregnancy outcomes were reported: 147 (91.3%) live births, 14 (8.7%) spontaneous abortions (< 22 weeks). In UK/Ireland, 9 outcomes were reported: all live births, 8 full term, none premature (details pending on 1 case). Globally, 4 adjudicator-confirmed birth defects were reported: pyloric stenosis (1), transposition of the great vessels (1), ventricular septal defect (2; 1 in UK/Ireland). No maternal, neonatal, perinatal, or infant deaths were reported.ConclusionsConsistent with previous reports, there was no safety signal for DMF exposure on pregnancy outcomes based on ongoing registry results.Support: Biogen; disclosures to be included on poster.

Pregnancy outcomes in patients in the alemtuzumab MS clinical development program (CAMMS223 and NCT00050778; CARE-MS I and NCT00530348; CARE-MS II and NCT00548405; CAMMS03409 and NCT00930553) were evaluated. Patients received 2 alemtuzumab courses in core studies (baseline, 5 days; 12 months later, 3 days), and optional, as-needed retreatment during extension per investigator discretion. Pregnant/lactating patients were treatment-ineligible but remained on study for safety follow-up. By December 31, 2015, 200 pregnancies occurred in 137/972 alemtuzumab-treated women, including 182 completed with known outcomes, 11 ongoing, and 7 unknown outcomes. Of completed pregnancies, 123 (68%) were live births without congenital abnormalities or birth defects; 39 (21%) spontaneous abortions, 19 (10%) elective abortions, and 1 (0.5%) stillbirth (previously reported). There was no evidence of teratogenicity, and the spontaneous abortion rate was comparable with other MS and general populations. Women are recommended to use effective contraception during alemtuzumab infusion and for 4 months after. Real-world data are currently collected by the International Lemtrada Pregnancy Exposure Registry, a prospective, noninterventional, observational safety study enrolling patients pregnant during or within 4 months of alemtuzumab exposure in ≥19 countries. It will evaluate pregnancy outcomes, including monitoring infants for adverse events for 1 year. UK pregnancy cases can be reported to: Neuroresearch.nurse@srft.nhs.uk; phone 0161-206-0534.Study Support Sanofi and Bayer HealthCare Pharmaceuticals.

In 2014, teriflunomide and dimethyl fumarate were approved by NHS regulators as first-line oral treatments for multiple sclerosis in England. We audited the safety, tolerability and treatment retention rates of the first line oral DMTs in Greater Manchester. Case notes of MS patients treated with first line oral DMTs were analysed for drug discontinuation reason, blood monitoring compliance and drug related side effects within the first 12 months of treatment. Of 39 patients, treated with teriflunomide, 89% were still on treatment at 12 months and reported very few side effects. 5% withdrew from treatment due to non-adherence with blood test monitoring, 3% due to lack of efficacy and 3% due to side effects. 273 patients treated with dimethyl fumarate, had a retention rate of 75% after 12 months. 12% discontinued treatment due to gastrointestinal side effects and 3% due to fatigue, headache and depression. Occasionally patients reported appetite/weight changes and altered hair appearances. 6% of patients were non-adherent with blood test monitoring. Lymphocyte drop below 0.5 for more than 3 months occurred in 2%, hence treatment was discontinued. Patient retention rate was better with teriflunomide than with dimethyl fumarate. Teriflunomide blood monitoring carries a significant administrative burden but it seems to be well tolerated in our cohort.