bluuebunny/crossref_metadata_2025_split huggingface dataset:
108  UK multiple sclerosis service and DMT audit of 70 centres: variation in DMT prescribing
Authors: Rog David , Mathews Joela , Hobart Jeremy ,   Raising the Bar 4 MS UK MS Study Group
Published: May 2022

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
109  UK multiple sclerosis service audit of 70 centres: observed staffing, proposed staffing, coping
Authors: Rog David , Jeremy Hobart , Joela Mathews ,   Raising the Bar for 4 MS UK Study Group
Published: May 2022

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
111  UK Multiple Sclerosis service audit of 70 centres: caseloads, patient lists and databases
Authors: Rog David , Hobart Jeremy , Mathews Joela ,   Raising the Bar 4 MS UK Study Group
Published: May 2022

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
113  Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients
Authors: Gärtner Jutta , Hauser Stephen , Bar-Or Amit , Montalban Xavier , Cohen Jeffrey , Cross Anne , Deiva Kumaran , Häring Dieter , Su Wendy ,   et al
Published: May 2022

ObjectiveTo evaluate the benefit-risk profile of ofatumumab treatment in patients with early relapsing multiple sclerosis (RMS) subgroup in Phase 3 ASCLEPIOS I/II trials.MethodsKey efficacy and safety outcomes were assessed in the newly diagnosed, treatment-naïve subgroup who received ofatumumab or teriflunomide as first-line therapy in the trials (n=615, 32.7% of total patients).ResultsCompared to patients on teriflunomide, ofatumumab reduced ARR by 50.3% (0.09 vs 0.18; p<0.001), 3mCDW risk by 38% (10.1% vs 12.8%; p=0.065), 6mCDW risk by 46% (5.9% vs 10.4%; p=0.044), gadolinium- enhancing T1 lesions/scan by 95.4% (0.02 vs 0.39: p<0.001), and new/enlarging T2 lesions/year by 82.0% (0.86 vs 4.78, p<0.001). Treatment-emergent adverse events (AEs) occurred in 84.7% ofatumumab vs 86.0% teriflunomide-treated patients; serious AEs were reported in 7.0% and 5.3%, respectively. Infection rates were comparable between ofatumumab (56.1%) and teriflunomide (56.5%); serious infection rates were 1.9% and 0.7%, respectively. 99.8% of injection reactions were mild-to-moderate; after the 4th injection, >70% RMS patients self-injected at home.ConclusionOfatumumab is the first anti-CD20 DMT that can be self-administered at home, as demonstrated in ASCLEPIOS. Here, ofatumumab showed superior efficacy vs teriflunomide with low absolute relapse rates, very low MRI lesion activity and prolonged time to disability worsening. Funding statement: This study was funded by Novartis Pharma AG, Basel, Switzerland.teresa.sawtell@novartis.com
114  Effect of siponimod on cognitive processing speed in SPMS patients with active and non-active disease
Authors: Penner K , Giovannoni G , Cree BAC , Fox RJ , Bar-ors A , Gold R , Vermesch P , Piani-Meier D , Ritter S ,   et al
Published: May 2022

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
121  Autoimmune autonomic neuropathy on the Adie spectrum: ‘Ross syndrome?’
Authors: Basgaran Amedra , McColgan Peter , Sacks Benjamin , Oommen Grace , Koay Shiwen , Alsukhni Rana , Hagen Ellen Merete , Ingle Gordon , Iodice Valeria , McNamara Patricia 
Published: May 2022

Ross syndrome is a rare syndrome of segmental autonomic dysfunction, characterised by a triad of tonic pupils, hyporeflexia and anhidrosis. We present an atypical case of such a patient, presenting with added features of cardiovascular autonomic dysfunction.Our case concerns a 66-year-old female, who experienced progressive stepwise deterioration in the functionality of her autonomic nervous system. Her symptoms began with a left Adie’s pupil, followed by a chronic dry cough and diarrhoea. The onset of anhidrosis and orthostatic hypotension subsequently occurred 30 and 40 years later, respectively.Autonomic function testing confirmed cardiovascular autonomic failure as well as deficiencies of sudomotor, salivary and tear function. Severe orthostatic hypotension was demonstrated along with an abnormal Valsalva response, and loss of the nocturnal circadian rhythm. Thermoregulatory and dynamic sweat testing further confirmed global anhidrosis.Our case highlights that patients do not always fit diagnostic criteria of eponymous syndromes, and usually demonstrate varying levels of autonomic dysfunction. We propose diagnosis of such atypical cases to be part of an Adie spectrum ganglionopathy, rather than attempting to fit into an eponymous syndrome phenotype. We further believe there to be an autoimmune basis to the Adie spectrum of disorders and have proposed immunotherapy as definitive management.a.basgaran@nhs.net|ABN Bursary
128  Variety is the splice of life
Authors: Knight KAW , McDonald JJ , Davenport RJ 
Published: May 2022

Case 1: A 42-year-old female presented with progressive exertional breathlessness over 2 years. She was breathless at rest and had bilateral Trendelenburg signs. Pulmonary function testing demonstrated a restrictive defect. Serum CK was elevated at 300. EMG demonstrated myotonia. We considered a wide differential, but a very low alpha glucosidase level led to genetic testing revealing GAA heterozygosity (c.-32–13T>G and c.1528G>A; p.(Trp516*) variants), confirming Pompe disease.Case 2: A 35-year-old female presented with a 20-year history of arm and leg weakness. Examination revealed proximal weakness affecting all four limbs but no respiratory involvement. Investigations dem- onstrated a raised CK of 1,000. Neurophysiology confirmed myopathic changes. An alpha glucosidase level was low on two occasions. Genetic testing confirmed GAA heterozygosity: (c.-32–13T>G variant and GAA exon 18 deletion) confirming Pompe disease.Pompe disease is an autosomal recessive condition caused by mutations in the GAA gene. Enzyme deficiency leads to impaired glycogen breakdown, with subsequent body tissue accumulation. GSD-II may present with varying phenotypes which are influenced by genotypic variations and level of enzyme activity, as these cases demonstrate. Diagnosis is important as enzyme replacement therapy is available. The clue is a low alpha-glucosidase level, a simple but crucial test to perform.kawknight@gmail.com89
130  Safety, β-sarcoglycan expression and functional outcomes from systemic gene transfer of rAAVrh74.MHCK7.SGCB in LGMD2E/R4
Authors: Rodino-Klapac Louise , Pozsgai Eric , Lewis Sarah , Griffin Danielle , Meadows Aaron , Lehman Kelly , Church Kathleen , Lowes Linda , Richardson James , Mendell Jerry 
Published: May 2022

Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is caused by β-sarcoglycan (SGCB) gene mutations, resulting in loss of functional protein and dystrophin-associated protein complex disruption. LGMD2E/R4 symptoms include hip/shoulder muscle weakness, cardiac involvement, and elevated creatine kinase (CK). Here, we report initial findings of a Phase 1/2 open-label, systemic gene transfer trial (NCT03652259) of rAAVrh74.MHCK7.hSGCB (SRP-9003), designed to restore functional SGCB, in patients with LGMD2E/R4. Six patients (aged 4–15 years, negative for rAAVrh74 antibodies, 100-meter timed test >40%) received a single SRP-9003 IV infusion of 1.85×1013 vg/kg (Cohort 1, n=3) or 7.41×1013 vg/kg (Cohort 2, n=3). Prednisone (1 mg/kg/day) was initiated 1 day before (30–60 days taper). Endpoints: safety (primary), SGCB expression (secondary), others: North Star Assessment of Limb-girdle Muscular Dystrophies (NSAD), timed functional tests. SRP-9003 is well tolerated with no unexpected immunologic responses observed. All patients demonstrated efficient transduction and robust SGCB expression post-infusion, with subsequent sarcoglycan complex reconstitution and CK reduction. Six months after SRP-9003 infusion, both patient cohorts experienced functional improvements. Cohort 1 had data available up to 18 months indicating NSAD and timed test improvements were maintained over time. These data suggest long-term efficacy of SRP-9003 gene-transfer therapy, supporting advancement of the clinical development program.jrichardson@sarepta.com90
133  Adherence to the ABN guidelines for the diagnosis and management of myasthenia gravis
Authors: Welch Joseph , Jacob Saiju 
Published: May 2022

BackgroundMyasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction causing fatigable muscle weakness.AimTo assess adherence to the ABN guidelines for the diagnosis and management of MG at University Hospital Birmingham (UHB) and compare to the previous 2010–2014 audit.MethodsClinic and discharge letters of patients diagnosed with MG from 2015–2019 including data were retrospectively analysed.Results66 patients diagnosed with MG from 2015–2019 were identified; 13/66 (20%) ocular, 53/66 (80%) generalised. Anti-AChR positive: 59/66 (89%). Tested for anti-MuSK antibodies: 6/66 (9.1%), in whom 3/6 (50%) were already anti-AChR positive. 30/66 (45%) patients had neurophysiology, 26 (87%) of whom were already anti-AChR positive. 1 patient with negative serology and neurophysiology did not receive MR brain. Mediastinal imaging: 59/66 (89%). 53/66 (80%) patients required glucocorticoids. 27/66 (41%) patients required IVIG and/or plasma exchange. 1 patient required rituximab. TPMT levels checked prior to commencing azathioprine: 23/23 (100%) vs. 71.4% in 2010–2014. Bone protection if on glucocorticoids: 51/53 (96%) vs. 90% in 2010–2014.ConclusionsDiagnosis and management of MG at UHB is generally in line with the ABN guidelines. TPMT testing and bone protection has improved since the 2010–2014 audit. Anti-MuSK and neurophysiology are often being used unnecessarily.josephwelch97@hotmail.com
007  The MS-STAT2 trial in secondary progressive MS – study design and update
Authors: Williams Thomas , John Nevin , Calvi Alberto , Doshi Anisha , Bianchi Alessia , Brownlee Wallace , Blackstone James , Braisher Marie , Anglias Floriana De , Chataway Jeremy 
Published: May 2022

The MS-STAT2 study is a Phase III, 3 year multi-centre, randomised, placebo-controlled trial assessing the efficacy of 80mg simvastatin vs. placebo in secondary progressive multiple sclerosis (SPMS). Building upon the promising results of the MS-STAT1 study, it is an academically led study funded through a collaboration of the NIHR HTA, MS Society (UK), National MS Society (US), and the Rosetrees Trust.Here we will provide an update on the trial design and progress, including:The agreed trial extension periodAdaptations to recruitment targets and trial designAn update on trial sites where patients can be referredAn update on current trial progressthomas.williams@nhs.net
135  CMT with renal impairment: consider a dip
Authors: Doherty Carolynne , Blake Julian , Skorupinska Mariola , Shah Sachit , Laura Matilde , Reilly Mary 
Published: May 2022

BackgroundWe describe two patients from our neuropathy cohort who have CMT with slowed conduc- tion velocities (CV) and renal involvement and discuss the importance of urine dipstick testing in those without a genetic diagnosis.Cases: A 19-year-old had deterioration in his running aged 3, required foot surgery aged 10 and scoliosis surgery aged 15. Distal atrophy and weakness with large fibre sensory impairment was evident. At age 12, neurophysiology demonstrated absent SAPs, reduced CMAPs and MCVs of 10–18m/s. Urine dipstick showed proteinuria. Whole genome sequencing demonstrated a previously described p.Cys104Tyr INF-2 mutation.(1) Another patient required renal transplantation attributed to scarlet fever in her 20’s. CMT was diagnosed age 11, again requiring foot surgery and scoliosis management. A NGS panel identified the previously described p.Val102Asp INF-2 mutation.(2)DiscussionMutations in INF-2 are associated with dominant nephrotic syndromes including Focal Segmental Glomerulosclerosis of varying severity, including needing renal transplants. CMT, typically inter- mediate, is not always present, with latest described onset age 28, and may precede renal involvement. As identification and management of nephrotic syndrome is crucial, we advocate urine dipstick testing in CMT patients who do not yet have a genetic diagnosis, particularly in the presence of slowed MCV.1) Bacquet J, et al.Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing:Molecular spectrum delineation. BMJ Open.2018;8(10):1–14. 2) Challis RC, et al. Thrombotic microangiopathy in inverted formin 2-mediated renal disease. JAmSocNephrol.2017;28(4):1084–91.carolynnedoherty@doctors.org.uk|NIHR Bursary
008  Systemic inflammatory response in relapsing-remitting multiple sclerosis
Authors: Varatharaj Aravinthan , Stuart Charlotte , Jurynczyk Maciej , Halfpenny Christopher , Kitley Joanna , Galea Ian 
Published: May 2022

Multiple sclerosis (MS) is often described as an inflammatory disease of the central nervous system (CNS). However, the aberrant immune response may not be fully compartmentalised within the CNS. Here we present two strands of evidence for an active systemic inflammatory process in MS. First, we describe a case series of six individuals with relapsing-remitting MS (RRMS) and sustained raised serum inflammatory markers. All displayed persistent leucocytosis and/or raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), with no evidence of any other systemic or alternative neuro-inflammatory condition on long-term follow-up. All but one met criteria for rapidly-evolving severe (RES) RRMS. We hypothesised that these cases reflect the extreme end of a systemic inflammatory response spectrum in MS. Therefore, we sought to further investigate the systemic inflammatory response in RRMS by a more sensitive method, namely liquid chromatography-mass spectrometry to detect urinary neopterin, a molecular product of activated macrophages and a non-specific marker of systemic inflammation. A separate group of individuals with RRMS showed significantly higher concentrations of urinary neopterin compared to age- and gender- matched healthy controls.a.varatharaj@soton.ac.uk
015  Reduced risk of secondary progressive multiple sclerosis by treatment with clad- ribine tablets: CLARITY study analysis
Authors: Vermersch Patrick , Giovannoni Gavin , Soelberg-Sorensen Per , Rammohan Kottil , Cook Stuart , Keller Birgit , Roy Sanjeev 
Published: May 2022

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
018  Disease control beyond NEDA: the value of non-clinical measures to determine treatment response to natalizumab
Authors: Calabresi Peter A , Kappos Ludwig , Giovannoni Gavin , Plavina Tatiana , Koulinska Irene , Edwards Michael R , Kieseier Bernd , Moor Carl de , Fisher Elizabeth 
Published: May 2022

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