bluuebunny/crossref_metadata_2025 huggingface dataset:
106  (NOT) comparing apples with apples; MS hospital episode statistics dashboard highlights variation in trusts’ reporting
Authors: Rog David , Hobart Jeremy , Clements Jake , McGregor Jamie , Mazibrada Gordon , Rajkumar Arthi , Mathews Joela
Published: May 2022

Introduction

GIRFT 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.

Methods

DR, 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.

Results

Consistent 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.

Conclusion

Trusts 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.

david

rog@srft.nhs.uk

78
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

Introduction

The UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address MS disease modifying treatment (DMT) prescribing.

Aim

To document MS Teams’ DMT prescribing.

Methods

We 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.

Results

To 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.

Conclusions

DMT 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.

Acknowledgements

Neurology Academy david.rog@srft.nhs.uk

79
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

Introduction

The UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address MS Team staffing and their levels of coping.

Aim

To 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.

Methods

MS 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.

Results

MS 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.

Conclusions

Staffing 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

Introduction

The UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address caseloads managed and use of databases.

Aim

To document the workload of MS Teams and how they record their patients.

Methods

We 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.

Results

70 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.

Conclusions

Enhanced 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

Objective

To evaluate the benefit-risk profile of ofatumumab treatment in patients with early relapsing multiple sclerosis (RMS) subgroup in Phase 3 ASCLEPIOS I/II trials.

Methods

Key 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).

Results

Compared 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.

Conclusion

Ofatumumab 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

Background

Siponimod 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).

Objectives

To evaluate the effect of siponimod on CPS in active (aSPMS) and non-active (naSPMS) patients from EXPAND core study.

Methods

This 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.

Results

Change in SDMT (95% Cl) versus placebo from baseline to M24 in aSPMS and naSPMS groups was

2.34 (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).

Conclusions

Siponimod was associated with relevant benefits in CPS as measured by change in SDMT in patients with active and non-active SPMS.

teresa

sawtell@novartis.com

82
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.com

89
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.com

90
133  Adherence to the ABN guidelines for the diagnosis and management of myasthenia gravis
Authors: Welch Joseph , Jacob Saiju
Published: May 2022

Background

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction causing fatigable muscle weakness.

Aim

To 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.

Methods

Clinic and discharge letters of patients diagnosed with MG from 2015–2019 including data were retrospectively analysed.

Results

66 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.

Conclusions

Diagnosis 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 period

Adaptations to recruitment targets and trial design

An update on trial sites where patients can be referred

An update on current trial progress

thomas.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

Background

We 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)

Discussion

Mutations 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

Background

Cladribine 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.

Methods

This 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).

Results

Proxy 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).

Conclusions

Risk 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:NCT00213135

g.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

Introduction

No 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.

Methods

We 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).

Results

No 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).

Conclusion

MRI 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
022  Updated safety of cladribine tablets in multiple sclerosis patients: integrated safety analysis and post-approval data
Authors: Cook Stuart , Giovannoni Gavin , Leist Thomas , Comi Giancarlo , Syed Sana , Nolting Axel , Damian Doris , Schick Regina , Jack Dominic
Published: May 2022

Background

This 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.

Methods

The 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).

Results

Patient 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.

Conclusions

No 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:NCT01013350

g.giovannoni@qmul.ac.uk
023  Relapse outcomes with natalizumab Q4W vs switch to Q6W
Authors: Butzkueven Helmut , Kappos Ludwig , Spelman Tim , Trojano Maria , Wiendl Heinz , Su Ray , Hyde Robert , Licata Stephanie , Ho Pei-Ran , Campbell Nolan
Published: May 2022

Introduction

The approved dosing of natalizumab (300 mg infusion every 4 weeks [Q4W]) is associated with risk of progressive multifocal leukoencephalopathy. This analysis from the TYSABRI Observational Program (TOP) compared relapse outcomes in patients who switched to natalizumab every 6 weeks (Q6W) after 1 year of Q4W with patients who remained on Q4W.

Methods

Eligible TOP patients had ≥1 year of natalizumab Q4W. Treatment duration-matched Q6W and Q4W patients (191 pairs) were compared by propensity score matching (PSM). Negative binomial model-estimated annualised relapse rate (ARR) and Kaplan-Meier-estimated relapse risk were compared during the post-switch and exposure-matched follow-up periods.

Results

After PSM, 135 pairs of Q6W and Q4W patients were included. Mean treatment duration was

4.4 years in both groups. There was no difference in ARR (Q6W: 0.231 [95% confidence interval (CI), 0.145–0.367]; Q4W: 0.254 [0.160–0.402]; P=0.774) or relapse risk (hazard ratio [95% CI], 1.021 [0.583–1.789]; P=0.940) between groups.

Conclusions

No significant difference in relapse outcomes was observed between patients who switched

4t6o Q6W and those who remained on Q4W. An ongoing randomized prospective trial of Q4W vs Q6W will inform further on the effectiveness of natalizumab Q6W. Support: Biogen.

peiran.ho@biogen.com
031  Long-term efficacy of ocrelizumab in primary progressive multiple sclerosis: 6.5-study years
Authors: Schmierer Klaus , Wolinsky Jerry S , Brochet Bruno , Hartung Hans-Peter , Naismith Robert , Koendgen Harold , Manfrini Marianna , Sauter Annette , Prajapati Kalpesh , Kappos Ludwig
Published: May 2022

Background

Efficacy/safety of ocrelizumab in primary progressive multiple sclerosis were demonstrated in the ORATORIO (NCT01194570) double-blind period (DBP). Here we assessed the efficacy of switching to, or earlier initiation of, ocrelizumab after 6.5-study years (312 weeks), in the open-label extension (OLE).

Methods

During the DBP, patients were randomised to ocrelizumab or placebo for ≥120 weeks until a prespecified number of confirmed disability progression (CDP) events occurred. Patients continued blinded treatment until the outcome was ascertained (extended controlled period [ECP]). At OLE initia- tion, patients continued ocrelizumab (OCR-OCR) or switched from placebo to ocrelizumab (PBO-OCR). Time to onset of 24-week-CDP and time-to-wheelchair-confinement (Expanded Disability Status Scale

≥7.0) were analysed.

Results

During the DBP, ocrelizumab reduced the risk of 24-week-CDP by 25% (p=0.037) vs placebo. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 24-week-CDP in PBO-OCR and OCR-OCR was 44.7% vs 33.3% (Δ=11.4%; p=0.005), and at Week 312 was 64.8% vs 51.7% (Δ=13.1%; p=0.002), respectively. During DBP+ECP+OLE, risk of wheelchair confinement was 42% lower (p=0.011) and of 24-week-CDP was 28% lower (p=0.002) in OCR-OCR vs PBO-OCR.

Conclusions

Compared with PBO-OCR, initiating ocrelizumab 3–5 years earlier significantly reduced the risk of wheelchair confinement and 24-week-CDP.

k.schmierer@qmul.ac.uk
035  Diagnosis of secondary progressive multiple sclerosis in UK centres: results from the SPECTRUM project
Authors: Duddy Martin , Wilkinson Carmel , Rhys Katherine , Medhurst Steve
Published: May 2022

Background

As new treatment approaches emerge for progressive forms of multiple sclerosis (MS), it is important to understand the factors underlying current practice.

Methods

We used a structured questionnaire to interview 59 healthcare professionals (HCPs) from geo- graphically-dispersed UK MS centres about current disease modifying therapy (DMT) management of patients with suspected/confirmed secondary progressive MS (SPMS).

Results

Of the HCPs who used a definition of SPMS, a minority used the Lublin 2014 phenotype criteria (n=2/36, 6%), the remainder used a variety of other definitions (n=34/36, 94%). The most important element considered for SPMS diagnosis was expanded disability status scale (EDSS) score increase and absence of relapse (n=21/59, 36%), however many other criteria were also used. The median estimated time between first suspecting and diagnosing SPMS was 12.0 months (IQR 12.0–24.0, n=45). The most common explanations for reluctance to diagnose SPMS were concerns over withdrawing DMTs (n=49/59, 83%) and psychological impact on patients (n=39/59, 66%).

Conclusions

There is substantial variation in the UK in how HCPs define and diagnose SPMS. Diagnosis is often made at advanced levels of disability and can take a year or longer from first suspicion of SPMS.

katherine.rhys@novartis.com
044  Safety and efficacy of dimethyl fumarate in ESTEEM UK cohort
Authors: Ford Helen L , Su Ray , Parks Becky , Syndercombe Fiona , Jones Cynthia J
Published: May 2022

Introduction

ESTEEM (NCT02047097) is an ongoing 5-year, global study characterizing long-term safety and effectiveness of routinely prescribed dimethyl fumarate (DMF) in multiple sclerosis (MS) patients. We report results from an analysis of the UK cohort of ESTEEM.

Methods

The primary objective of ESTEEM is to assess the incidence, type, and patterns of serious adverse events (SAEs), and AEs leading to discontinuation of DMF in routine practice. Secondary objectives include assessment of annualized relapse rate (ARR) and proportion of patients without relapse at 6 and 12 months.

Results

Of 238 UK patients (median age 42 years, 187[79%] female), SAEs were reported in 14(6%) patients. AEs leading to discontinuation occurred in n=53(22.3%) patients; the most common of these were gas- trointestinal disorders (n=20;8.4%). Unadjusted ARR declined by 84%(95%confidence interval [CI]=68– 100%;P<0.0001), from 0.74(95%CI=0.63–0.85) 12 months before enrollment to 0.12(95%CI=0.07–0.16) the year after enrollment. The proportion of relapse-free patients was 93.8%(n=223) and 87.9%(n=209) at 6 and 12 months, respectively.

Conclusions

No new safety signals were observed in patients treated with DMF routinely for one year. ARR was significantly reduced vs the year prior to enrollment. Safety/efficacy results were similar between the UK and overall ESTEEM populations.

Support

Biogen; disclosures detailed on poster.

fiona.syndercombe@biogen.com
045  Effect of siponimod on cortical grey matter and thalamic volume in secondary progressive multiple sclerosis
Authors: Arnold Douglas L , Fox Robert J , Bar-Or Amit , Cree Bruce AC , Giovannoni Gavin , Gold Ralf , Vermersch Pat- rick , Meier Daniela Piani , Arnould Sophie , Kappos Ludwig
Published: May 2022

Background

Grey 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).

Methods

Magnetic 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.

Results

In 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.

Conclusions

Siponimod significantly reduced cGM and thalamic volume loss compared with placebo in patients with SPMS.

g.giovannoni@qmul.ac.uk
049  Hypertension is uncommon during alemtuzumab treatment for relapsing-remit- ting multiple sclerosis
Authors: Ong Hui Ching , Shields Aoife , Leary Siobhan , Brownlee Wallace J
Published: May 2022

Background

Haemorrhagic cerebrovascular events have been reported during Alemtuzumab treatment for relapsing-remitting multiple sclerosis (RRMS) leading to changes in the marketing authorisation in Europe. Hypertension is the proposed mechanism.

Aims

To characterise systolic blood pressure (SBP) changes during Alemtuzumab administration and the frequency of significant hypertension.

Method

We recorded SBP measurements during Alemtuzumab infusions from a random sample of RRMS patients. Mean SBP changes were calculated for each day and the 5-day treatment course. Common Terminology Criteria for Adverse Events was used to grade hypertension.

Results

2412 SBP measurements from 50 RRMS patients (mean age 35.9 years; 70% female) were recorded. No patients had premorbid hypertension. The mean (SD) SBP change was -0.7 (7.59) mmHg over 5 days. Two (4%) patients developed sustained grade III hypertension (SBP ≥160mmHg) over two or more readings >15 minutes apart, which resolved spontaneously. No patients had immediate cerebrovascular complications.

Conclusions

Clinically-significant hypertension is uncommon during Alemtuzumab treatment and should prompt close clinical observation. Slowing (or stopping) the rate of infusion should be considered in patients with sustained hypertension.

hui.chingong@nhs.net
054  The individual costs of multiple sclerosis
Authors: Nicholas R , Middleton R , Tuite-Dalton K , Rogers W , Craig E , Chevli M , Pulikottil-Jacob M , Heaven M
Published: May 2022

Background

The UK Multiple Sclerosis Register (UKMSR) captures data from multiple sources including directly from people with MS (pwMS) via online questionnaires. There is little research into the non-medical (personal) costs of MS. In partnership with Sanofi we investigated healthcare resource use and costs (excluding drugs), including who bears these costs, by disease severity and type

Methods

A cost of illness questionnaire was deployed to 3035 pwMS on the UKMSR. Respondent’s answers were linked to retrospective UKMSR data. Resource consumption was categorised as being direct (medical) or indirect (non-medical) and costed by NHS and Social Services estimates for 2018.

Results

£509,003 was calculated as non-medical costs over a year and £435,488 in medical costs generated over 3 months (n=537, 6935 interventions). PwMS reported self-funding 75% of non-medical costs these were mainly home modifications. Costs, increased with disability but those with indirect costs (n=138) had higher medical costs, were more disabled and were more likely to be unemployed than those with medical interventions only (n=399).

Conclusions

The importance of disability in driving costs is again clearly illustrated with balance between indirect and direct costs consistent with the UK health environment as a whole. PwMS and their families fund 75% of non-medical costs that can facilitate early discharge and reduce the need to rehabilita- tion/nursing home services.

richard.nicholas@btinternet.com
059  Secondary progressive MS in the UK: a prospective cohort study
Authors: Harding Katharine , Joseph Fady , Pickersgill Trevor , Tomassini Valentina , Tallantyre Emma , Robertson Neil
Published: May 2022

Background

Although most people with relapsing onset multiple sclerosis (R-MS) eventually transition to secondary progressive multiple sclerosis (SPMS), little is known about disability progression in SPMS.

Methods

All R-MS patients in the Cardiff MS registry were included. Cox proportional hazards regression was used to examine a) hazard of converting to SPMS and b) hazard of attaining EDSS 6.0 and 8.0 in SPMS.

Results

1611 R-MS patients were included. Older age at MS onset (hazard ratio [HR] 1.02, 95%CI 1.01–1.03), male sex (HR 1.71, 95%CI 1.41–2.08), and residual disability after onset (HR 1.38, 95%CI 1.11–1.71) were asso- ciated with increased hazard of SPMS. Male sex (EDSS 6.0 HR 1.41 [1.04–1.90], EDSS 8.0 HR 1.75 [1.14–2.69]) and higher EDSS at SPMS onset (EDSS 6.0 HR 1.31 [1.17–1.46]; EDSS 8.0 HR 1.38 [1.19–1.61]) were associated with increased hazard of reaching disability milestones, while older age at SPMS was associated with a lower hazard of progression (EDSS 6.0 HR 0.94 [0.92–0.96]; EDSS 8.0: HR 0.92 [0.90–0.95]).

Conclusions

Different factors are associated with hazard of SPMS compared to hazard of disability progres- sion after SPMS onset. These data may be used to plan services, and provide a baseline for comparison for future interventional studies and has relevance for new treatments for SPMS

RobertsonNP@cardiff.ac.uk
061  T cell-mediated cerebellitis after ipilimumab for small cell lung cancer
Authors: Guillochon Remi , Nolan Luke , Nicoll James , Jogai Sanjay , Joseph-Pietras Deborah , Arriola Edurne , Ottensmeier Christian , Galea Ian
Published: May 2022

Ipilimumab is an anti-CTLA4 antibody in evaluation for the treatment of small cell lung cancer. We report a case of rapidly progressive fatal cerebellitis occurring eight months after first dosing. Pre-treatment weakly positive anti-Yo antibodies did not change. Clinically asymptomatic anti-voltage-gated calcium channel antibodies developed after ipilimumab treatment, despite lack of expression by the tumour. The patient died three weeks into the neurological illness. Post-mortem examination revealed a T cell-mediated cerebellitis, with CD8 cytotoxicity towards Purkinje cells. This demonstrates the potential for CD8 T cells to trigger neuronal autoimmunity, offering insight into the early events in paraneoplastic neurological disease.

remi.guillochon@nhs.net
062  A case of autoimmune facial swelling, weakness and sensorineuropathy with lower limb myositis
Authors: Ur Rashid Sk Mamun , Warner Graham
Published: May 2022

Background

Clinical features of Sjögren’s Syndrome (SS) and Systemic Lupus Erythematosus (SLE) often overlap. We present a case with facial sensory neuropathy & myositis.

Clinical presentation: A 45-year-old lady with 14 years of fleeting myalgia/polyarthralgia, recurrent chest infections, oral ulcers, hair loss, and recent onset jaw and facial pain was initially diagnosed as having GCA/PMR but unresponsive to prednisolone. Developing new slurred speech, salivation pain, left facial weakness and vomiting a year later, SLE was diagnosed (investigations below). Neurological scrutiny five months after found bilateral sensory trigeminal neuropathy, asymmetric bifacial weakness, and ten- derness of TMJs, overlying the mandibular rami, shoulders, and extremities but no neurological deficits beyond painful dysarthria.

Immunology showed a raised ESR, a positive ANA, anti-Ro and anti-La with negative antiphospholipid antibodies. Initial testing reported normal CT chest and brain MRI but mild lymphocytic infiltration on temporal artery biopsy. Biochemistry showed CK of 2300 with upward trend. MRI and EMG showed myositis in hamstrings, quadriceps and adductors. PET-CT did not show any occult neoplasms. Retrospectively initial MRI revealed enlarged bilateral parotid glands well before serology testing.

Conclusion

Major salivary gland enlargement occurs in 25%-66% of primary-SS. These are rare with sec- ondary-SS yet best explain facial clinical phenomena here.

Myositis overlaps between SS and SLE but commoner with primary-SS. It is uncommon in lupus. SLE can have diffuse symptoms, including alopecia, oral ulcers and neuropsychiatric symptoms.

skmamunur@yahoo.co.uk
Dark matter and low scale leptogenesis in a flavor symmetric neutrino two Higgs doublet model ($$\nu $$2HDM)
Authors: Sarma Lavina , Boruah Bichitra Bijay , Das Mrinal Kumar
Published: May 2022

We have studied dark matter (DM) phenomenology, neutrinoless double beta decay (NDBD) and realized low scale leptogenesis in an extension of Standard Model (SM) with three neutral fermions, a scalar doublet and a dark sector incorporating a singlet scalar and a Dirac singlet fermion. A generic model based on $$A_4\times Z_4$$

A
4

×

Z
4

flavor symmetry including five flavons is used to explain both normal and inverted hierarchy mass patterns of neutrino and also to accommodate the dark matter mass. In this extension of the $$\nu $$
ν
2HDM, the effective neutrino mass observed in $$0\nu \beta \beta $$

0
ν
β
β

is well within the experimental limit provided by KamLAND-ZEN. In order to validate DM within this model, we have checked relic abundance and free streaming length of the dark sector component, i.e. a Dirac singlet fermion constraining its mass in keV range. More importantly we have also realised low scale leptogenesis simultaneously within this framework and also the Dirac CP phase gets constrained with the results. Bound from LFV is also incorporated in order to constrain the Yukawa couplings. More importantly, we have analyzed the dependence of various phenomenology with decay parameter for different choice of arbitrary complex angles.
Linear Nash-Greene fluctuations on the evolution of $$S_8$$ and $$H_0$$ tensions
Authors: Capistrano Abraão J. S. , Cabral Luís A. , Marão José A. P. F. , Coimbra-Araújo Carlos H.
Published: May 2022

We present the perturbation equations in an embedded four space-time from the linear Nash-Greene fluctuations of background metric. In the context of a five-dimensional bulk, we show that the cosmological perturbations are only propagated by the gravitational tensorial field equation. In Newtonian conformal gauge, we study the matter density evolution in sub-horizon regime and on how such scale may be affected by the extrinsic curvature. We apply a joint likelihood analysis to the data by means of the Markov Chain Monte Carlo (MCMC) method for parameter estimation using a pack of recent datasets as the Pantheon Supernovae type Ia, the Baryon Acoustic Oscillations (BAO) from DR12 galaxy sample and Dark Energy Survey (DESY1). We discuss the tensions on the Hubble constant$$H_0$$H0and the growth amplitude factor$$S_8$$S8of the observations from Planck 2018 Cosmic Microwave Background (CMB) and the local measurements of$$H_0$$H0with Hubble Space Telescope (HST) photometry and Gaia EDR3. As a result, we obtain an alleviation below$$\sim 1\sigma $$∼1σin the contours ($$S_8$$S8-$$\varOmega _m$$Ωm) at$$68.4\%$$68.4%confidence level (CL) when compared with DESY1 data. On the other hand, the$$H_0$$H0tension persists with$$\sim 2.6\sigma $$∼2.6σat$$68.4\%$$68.4%CL and$$1.95\sigma $$1.95σat$$95.7\%$$95.7%CL, aggravated with the inclusion of BAO data.
Higgs boson production at the LHC: fast and precise predictions in QCD at higher orders
Authors: Camarda Stefano , Cieri Leandro , Ferrera Giancarlo , Urtasun-Elizari Jesús
Published: May 2022

We present a new numerical program, , which provides fast and numerically precise predictions for Higgs boson production cross sections. The present version of the code implements the perturbative QCD expansion up to the next-to-next-to-leading order also combined with the resummation of the large logarithmic corrections at small transverse momenta up to next-to-next-to-leading logarithmic accuracy and it includes the Higgs boson production through gluon fusion and decay in two photons with the full dependence on the final-state kinematics. Arbitrary kinematical cuts can be applied to the final states in order to obtain fiducial cross sections and associated kinematical distributions. We present a benchmark comparison with the predictions obtained with the numerical programs and programs for which represents an improved reimplementation.
On SU(2)CS-like groups and invariance of the fermionic action in QCD
Authors: Catillo Marco
Published: May 2022

In this work, we introduce some new U(1) symmetry groups of the free fermionic action in Euclidean space–time, which are a consequence of parity and time-reversal symmetries. Afterwards, we discuss how the introduction of a gauge interaction affects the invariance of the action, with special reference to QCD. Moreover, inspired by recent QCD lattice results of Glozman et al., in which an interesting and unexpected symmetry group has been observed, namely [Formula: see text] (that contains [Formula: see text] as subgroup), we build other [Formula: see text]-like groups in Euclidean space–time using the previously introduced U(1) groups. Finally we argue about the possible invariance of the fermionic action with respect these new [Formula: see text]-like groups and its consequence on the hadron temporal correlators.