bluuebunny/crossref_metadata_2025 huggingface dataset:
117  Sustained and rapid B-cell depletion with ofatumumab: population pharma- cokinetic B-cell modeling in relapsing MS patients
Authors: Graham Gordon , Kahn Joseph , Savelieva Marina , Yu Huixin , Pingili Ratnakar , Willi Roman , Ramanathan Krishnan , David Olivier , Häring Dieter , Bagger Morten
Published: May 2022

Objectives

To characterize the pharmacokinetic (PK) relationship of ofatumumab for B-cell counts in RMS patients, assess the PK and B-cell dynamics given the Phase 3 dose regimen through PK-B-cell simulations and explore the effect of covariates on PK and B-cells.

Methods

The PK-B-cell model was developed using data from Phase 2 and 3 trials. Simultaneous fitting was performed to assess the interaction between PK and B-cells. Effect of body weight, age, administra- tion route, s.c. injection device, and baseline B-cell count on PK and B-cell parameters were evaluated.

Results

In total, 9,168 plasma concentrations from 1,440 patients were included in PK analysis and 17,158 B-cell counts from 1,486 patients in B-cell analysis. Simulations demonstrated a rapid, median B-cell depletion to <10 cells/µL in 8.75 days; no signs of B-cell repletion occurred between doses, and >94% of patients had <10 cells/µL at B-cell steady state and pre-dose. Regardless of weight, all patients achieved low B-cell counts, similar to results observed in Phase 3 trials. Baseline age, B-cell counts and injection device had negligible effect on PK parameters.

Conclusion

The PK-B-cell model showed early, rapid, and sustained B-cell depletion with ofatumumab, confirming the rationale for the chosen Phase 3 dosing regimen.

Funding statement.This study was funded by Novartis Pharma AG, Basel, Switzerland. teresa.sawtell@novartis.com
120  The impact of socioeconomic status and comorbidities on emergency admissions in patients with multiple sclerosis
Authors: Dobson Ruth , Chico Dan , Evans Rosanna , Reyes Saúl , Ford Helen , Giovannoni Gavin , Altincatal Arman , Vonsy Jean
Published: May 2022

Introduction

Socioeconomic status (SES) is a major determinant of health outcomes. This study explored the relationship between SES, comorbidities, and emergency admissions in people with multiple sclerosis (pwMS).

Methods

National Health Service England data from the Hospital Episodes Statistics (HES) database were used. Socioeconomic deprivation was assessed using the English Index of Multiple Deprivation.

Results

In 2019–2020, 6,210 of 36,765 pwMS in England (16.9%) were classified as “most deprived” (+29.1% versus 2015–2016). Of these most deprived pwMS, 17.8% had an emergency admission. Across 25 des- ignated Neuroscience Centres, the percentage of “most deprived” pwMS ranged from 3.0%-34.0% and the percentage of “most deprived” pwMS with emergency admissions ranged from 0%-47.6%. In England, diagnoses more common in emergency MS admissions (compared to all MS admissions) included pneumonia, sepsis, intestinal disorders, decubitus ulcer/pressure area, and disorders of fluid, electrolyte, and acid-base balance. Factors associated with deprivation (type 2 diabetes, hypertension, smoking) were seen across all MS admissions.

Conclusions

The proportion of “most deprived” pwMS and the proportion of “most deprived” pwMS with emergency admissions varied widely across centres. MS- and deprivation-related comorbidities were observed in emergency admissions of pwMS, highlighting the importance of addressing these issues.

Support

Biogen. Disclosures: Included in poster. jean.vonsy@biogen.com

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124  Symptoms of post-traumatic stress disorder are common after being diagnosed with multiple sclerosis
Authors: Giovannoni Gavin , Pepper George , Sloan Rob , DiMauro Sophie , Thompson Emily
Published: May 2022

Introduction

People with multiple sclerosis (PwMS) commonly describe being diagnosed with MS as traumatic. We did a web survey of pwMS to ascertain how many have symptoms compatible with post- traumatic stress disorder (PTSD) and how many have been diagnosed with PTSD.

Methods

A web survey was conducted from the 18-Dec-20 to the 4-Jan-21 via the shift.ms platform. Shift. ms is a social network of 38,000 pwMS. Data were collected anonymously.

Results

1079 pwMS (78% female, mean age of 48.3yrs) with an average disease duration since diagnosis of 15.7yrs completed the survey. 58.1% of respondents reported symptoms associated with PTSD in relation to MS. Only 18.1% of respondents had received a formal diagnosis of PTSD. Comments highlighted how the diagnosis of MS was given by a healthcare professional (HCP) as being a major factor in triggering PTSD-like symptoms.

Conclusions

PTSD-like symptoms and PTSD are common in pwMS and may be attributable to the way the diagnosis of MS is made. It is important that HCPs are aware of this problem and use empathetic com- munication techniques to try and mitigate against PTSD in this vulnerable group of people.

g.giovannoni@qmul.ac.uk

87
006  Secondary amenorrhea related to natalizumab
Authors: Obeng Laurenda , Brown Heather , Wheately Trevor , Good Catriona , Fisniku Leonora
Published: May 2022

Background

Adverse events are inevitable for many pharmacological interventions, including disease modifying treatment (DMT) in Multiple Sclerosis (MS). Amenorrhoea was reported in less than 2% in phase 3 trials of Natalizumab. Isolated cases have also been reported post marketing.We present a patient who developed secondary amenorrhoea linked to Natalizumab treatment for her relapsing-remitting MS (RRMS).

Case

A 36 year old female with highly-active RRMS was started on Natalizumab in June 2014. She developed secondary amenorrhoea by July 2014. Her blood results show low LH, normal FSH and low oestrogen and progesterone and normal thyroid function tests. She remained on Natalizumab for a year and her MS was stable. Due to continuing amenorrhoea Natalizumab was stopped and 3 months later she started menstruating regularly. Her hormonal changes were also normalised. Review of all her imaging from July 2014 – September 2016 revealed no evidence of a pituitary or hypothalamic abnormality or patho- logical enhancement. Patient was subsequently treated with Alemtuzumab and has remained stable.

Conclusion

Whereas a simple temporal association between a drug use and a particular event does not necessarily indicate a direct causal relationship, the occurrence of amenorrhoea in our patient linked to the start of Natalizumab and its resolution 3 months post treatment cessation, is too good of a coincidence to be fully dismissed.

leonora.fisniku@nhs.net
125  Towards an optimal multiple sclerosis patient case-load for a full-time MSologist
Authors: Giovannoni Gavin , Hobart Jeremy , Mazibrada Gordon , Bateman Karen , Marta Monica
Published: May 2022

Introduction

Strategy, evidence and anticipation should underpin workforce-planning.

Aim

To estimate a sustainable patient-caseload (PCL) for a full-time equivalent MS specialist neurologist (FTE-MSologist).

Methods

Hypothetically, an FTE-MSologist refers to 10-MSology-related programmed activities per week. We considered three service models (core, aspirational, alternative/DGH) with differing frequency, duration and content of patient consultations and monitoring. We computed the ideal number of new patients and existing patients, for each scenario, from detailed qualitative interviews with 4 MSologists at different NHS Trusts. Computations assumed all 3 scenarios had common support from MS nurses (@315 PLwMS/FTE MS nurse), MS coordinators, neuroradiology, neuropharmacist and administration.

Results

Estimates for 1-FTE-MSologist/year/service model were: Core: new-PCL=81 (range=46–115); existing- PCL=798 (range=672–923). Aspirational: new-PCL=21 (range=28–69); existing-PCL=481 (range=401–561). Alternative/DGH: new-PCL=89 (range=51–126); existing-PCL=874 (range=733–1015).

Conclusions

These MS PCL/FTE-MSologist estimates enable future NHS manpower planning to optimally staff specialist MS services. It is notable that few (if any) UK MS services have the support considered pre- requisite. Much of the direct clinical care work undertaken is “unseen” and not formally job-planned. These results have significant implications formal time and motion studies may be required to improve estimates’ accuracy.

Support.Karen Bateman was supported by Novartis. Disclosures: See poster g.giovannoni@qmul.ac.uk
127  ACTA1 associated myopathy with neurogenic EMG changes
Authors: Doherty Carolynne , Blake Julian , Manzur Adnan , Wakeling Emma , Shah Sachit , Muntoni Francesco , Reilly Mary
Published: May 2022

Background

We describe a proband and her son who have proximal limb and facial weakness and marked hand involvement. A congenital myopathy panel demonstrated two RYR1 variants and the p.Ile289Phe novel variant in ACTA1.

Cases: The proband had initially been diagnosed with SMA following premature birth, late milestones, scoliosis and proximal and distal weakness which was relatively static until age 40. EMG as a child was neurogenic. Her son had poor feeding after birth, delayed motor milestones, intellectual delay, and by his teens, severe facial weakness and distal upper limb wasting particularly the finger flexors and extensors, with hip flexion of grade 3. Repeat neurophysiological evaluation of the proband at age 60, demonstrated a neurogenic pattern but also brief polyphasic motor units, raising suspicion of an addi- tional myopathic process.

Discussion

Zukosky and colleagues1also described a family with a different missense mutation in the ACTA1 gene who had been diagnosed with SMA on the basis of neurogenic EMG findings. Our additional family confirms that myopathy can be accompanied by neurogenic EMG changes in ACTA1 associated myopathy.

Reference

1. Zukosky K, Meilleur K, Traynor BJ, Dastgir J, Medne L, Devoto M, et al. Association of a Novel ACTA1 Mutation With a Dominant Progressive Scapuloperoneal Myopathy in an Extended Family. JAMA Neurol. 2015 Jun 1;72(6):689–98.

carolynnedoherty@doctors.org.uk|NIHR Bursary
129  Limb girdle muscular dystrophy R12 (LGMD 2L, anoctaminopathy) presenting as refractory myositis: a case series
Authors: Marago Italo , Chinoy Hector , Roberts Mark , Roncaroli Federico , Duplessis Daniel , Marini-Bettolo Chiara , Lilleker James
Published: May 2022

The idiopathic inflammatory myopathy (IIMs) are a rare heterogenous group of immune-mediated diseases leading to muscle inflammation. Prompt and accurate diagnosis is important so that immunosuppressive treatment can commence and irreversible tissue damage be avoided. Other rare conditions may mimic IIM, making confirmation of diagnosis sometimes difficult.

Limb girdle muscular dystrophy type R12 (LGMD 2L, anoctaminopathy) is a recessive genetic myopathy which may present in adulthood and is caused by pathogenic variants in the ANO5 gene. Clinical pres- entation can vary from asymptomatic hyper-CK-aemia to exertional myalgia and/or progressive muscle weakness.

Here we present four cases of genetically confirmed LGMD R12 who were initially misdiagnosed with IIM. In each case treatment with immunosuppressants, >15 years in one case, was observed without a clear therapeutic response. All patients were negative for anti-nuclear antibodies and all myositis-associated/specific autoantibodies for which testing is available. Prominent fatty infiltration and selective pattern of muscle involvement on muscle magnetic resonance imaging was also observed.

The diagnosis of IIM must be carefully considered in autoantibody-negative patients. Adult-onset genetic myopathies, particularly LGMD R12, are differential diagnoses. Avoidance of potentially harmful immu- nosuppressive therapies, genetic counselling, and involvement in research are key benefits of accurate diagnosis in such cases.

italo.marago@nhs.net
131  Pooled safety data from the risdiplam clinical trial development programme
Authors: Servais Laurent , Baranello Giovanni , Chiriboga Claudia , Darras Basil , Bader-Weder Silvia , Gorni Ksenija , Jaber Birgit , McIver Tammy , Scalco Renata ,   et al
Published: May 2022

Risdiplam is a centrally and peripherally distributed oral survival of motor neuron 2 (SMN2) pre mRNA splicing modifier that increases the levels of functional SMN protein. Risdiplam (EVRYSDI™) has been approved by the US Food and Drug Administration for the treatment of patients with spinal muscular atrophy (SMA), aged 2 months and older. The risdiplam clinical development programme consists of four studies in a broad population of individuals with SMA.

FIREFISH (NCT02913482) and SUNFISH (NCT02908685) are two-part studies assessing safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy in infants with Type 1 SMA and patients with Type 2/3 SMA, respectively. JEWELFISH (NCT0302172) assesses safety, tolerability, PK and PD in patients with SMA who previously received RG7800 (R06885247), nusinersen (SPINRAZA®), olesoxime or onasemno- gene abeparvovec-xioi (ZOLGENSMA®). RAINBOWFISH (NCT03779334) assesses efficacy, safety, PK and PD in infants with genetically diagnosed and presymptomatic SMA.

Pooled analyses of FIREFISH and SUNFISH Parts 1 and 2 and JEWELFISH were conducted to determine the long-term safety profile of risdiplam. At the data-cut (15th January 2020) no treatment-related safety findings led to withdrawal from up to 39 months’ risdiplam treatment in 465 patients. Here we will present updated pooled safety analyses for the risdiplam studies.

g.baranello@ucl.ac.uk
132  Thymectomy for myasthenia gravis in the West of Scotland: a retrospective study
Authors: Fenech Valentina , Kirk Alan , Carmichael Caroline , Farrugia Maria Elena
Published: May 2022

The international thymectomy trial (MGTX) demonstrated benefits in myasthenia gravis (MG) patients without thymoma and up to the age of 65 years. This data and the increased availability of minimally invasive thymectomy surgery has resulted in an increasing number of patients being referred for thymec- tomy. We evaluated the clinical outcomes after thymectomy in 61 MG patients with or without thymic epithelial tumours (TET) from the West of Scotland Myasthenia database over a 10-year period.

All patients had positive acetylcholine receptor antibodies. Twenty-five (41%) patients were male. Fifty-five (90.2%) had generalised MG (27 patients with TET [TET-MG], all thymoma except for one with squamous cell thymic carcinoma; 28 patients without TET [non-TET-MG]) and 6 (9.8%) had ocular MG (including 3 TET-MG patients with thymoma). Overall, age at onset and diagnosis were comparable, with a lower median age at onset for female MG patients without TET. More severe symptoms at onset and at nadir were noted in TET-MG patients.

MGFA-post intervention status was similar in both groups, although more MG relapses were observed in the TET-MG group. TET-MG patients had slightly worse disease severity and outcomes. However, the two groups were largely comparable in their MG status and the therapies they received.

vally

fenech@gmail.com

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134  A qualitative study of patient perceptions of immunoglobulin treatment regimens for inflammatory neuropathy
Authors: Callanan E , Levee V , Compton L , Ramdharry G , Lunn M , Carr A
Published: May 2022

Introduction

With RCT evidence of equivalency between intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin in the management of CIDP, we sought to optimise uptake of homecare SCIg in our inflammatory neuropathy cohort. This is of particular importance in the context of the COVID pandemic.

Aim

To explore patient perception of IVIg and SCIg and understand treatment preferences.

Methods

We performed a non-hypothesis driven qualitative study of patient perception. Data was collected from adult patients with CIDP via an open-ended telephone interview and a focus group facilitated by medics independent members of the treating team. The data was coded using Braun and Clarke’s reflexive thematic analysis.

Results

11 patients were interviewed (mean age=51.55; S.D. 8.70, mean time on immunoglobulin treatment 61 months, S.D. 35.64). Patients found the treatment effective but highlighted perceived side-effects. The hospital environment (IVIg treatment) was reassuring but brought with it a range of difficulties, both logisti- cal and financial. Knowledge and direct experience of SCIg was lacking.

Conclusion

We will develop a structured questionnaire based on these themes for broader application across the cohort. From this qualitative data we will continue to adapt our service in a patient focused manner and identify measures of quality improvement.

emma

callanan1@nhs.net

92
137  Outcome measures in CMT: case examples from the muscle MRI in CMT study
Authors: Doherty Carolynne , Zuccarino Riccardo , Howard Pagie , McDowell Amy , Wastling Stephen , Laura Matidle , Thedens Daniel , Thornton John , Shy Micheal , Reilly Mary
Published: May 2022

Background

Twelve month increase in muscle fat fraction(FF) at calf has been demonstrated in patients with CMT1A.(1,2) Our MDA funded study builds on our previous work by investigating this method in patients with the three next most common subtypes of CMT: due to mutations in GJ1B, MPZ, and MFN2.

Methods

Sixty participants and 30 controls have been recruited. In select examples, baseline and follow-up FF were calculated at mid-calf and mid-thigh.

Results

A 45-year-old male with a MPZ mutation had imaging age 35 (CMTES 17), with FF at calf 20.9%. At age 45, CMTES was 20 and calf FF 35.6%. In a 32-year-old male with GJB1, CMTES rose from 9 to 10 at 12 months, with all muscle mid-calf FF rising from 9.5% to 11.8%. In the left peroneus longus, FF increased from 26% to 55% correlating with reduced ankle plantarflexion power. In a MFN2 patient, baseline CMTES was 16 and at 12-months 17. FF increased at thigh level from 10.5% to 15%.

Discussion

We present three cases illustrating key points from the study and demonstrate an increase in FF at 12 months in one patient each with CMT1X and CMT2A, and over 10 years in a patient with CMT1B.

carolynnedoherty@doctors.org.uk|NIHR Bursary
138  Frey’s syndrome: a review of the aetiology and possible role of neurotrophic factors
Authors: Hignett Sarah , Judd Owen
Published: May 2022

Frey’s syndrome describes the phenomenon of gustatory sweating and is a cause of significant social embarrassment for sufferers. It has been attributed to aberrant growth of parasympathetic salivatory fibres in the auriculotemporal nerve towards overlying sweat glands. However, the exact mechanism behind this growth is unknown.

Frey’s syndrome is a common sequela of parotidectomy and is usually preceded by trauma to the auricu- lotemporal nerve. In some neonates, however, Frey’s syndrome presents with no history of nerve injury. In these patients, the underlying trigger for Frey’s syndrome is unclear.

A review of the recent literature on nerve regeneration after injury and on nervous development in utero was conducted with the aim of developing further insights into the aetiology of both adult onset and paediatric Frey’s syndrome.

Neurturin, a neurotrophic factor released by both salivary and sweat glands, was identified as a possible key player in the aetiology of Frey’s syndrome. This factor is released both in utero and after nerve damage, so could connect the two presentations of gustatory sweating.

Further research into the role of neurturin could help to elucidate the pathogenic mechanisms underly- ing the condition and might reveal neurturin to be a potential target for pharmacological intervention um16sh@leeds.ac.uk

94
140  Baseline variation in commonly used inflammatory neuropathy clinical outcome measures
Authors: Keh Ryan , Lilleker James , Lavin Tim , Gosal David , Compton Laura , Kapoor Mahima , Carr Aisling , Lunn Michael
Published: May 2022

Background

Reliable outcome measures are vital for guiding immunoglobulin therapy in inflammatory neuropathy. Disease-specific outcome measures exist with statistically sound minimal clinically important difference (MCID) to detect change (I-RODS:+/-4; grip strength:+/-8kPa). Scores generally remain stable in well-treated disease but variation occurs.

Aims

To appreciate random variability of serially assessed grip strength, RODS and MRC-SS in clinically stable CIDP/MMN patients and explore early identification of non-random trends.

Methods

We performed a longitudinal study of serial outcome measures from Manchester neurosciences immunoglobulin database (June 2009 - September 2012). We used first score on maintenance dosing as baseline, and increase in dose (g/kg/month) as indicative of meaningful clinical deterioration. We cal- culated mean/SD actual and percentage change(Δ) for grip(kPa), I-RODS(logit scale) and MRC-SS(/70) over periods of clinical stability.

Results

54/152 patients had sufficient stability: 39CIDP (9F), 15MMN (2F). Median age:66 years(mean:64.8, range:28–89). ΔRODS: 313 timepoints over 0.4–83.9months (median:27.4). Median change:0(0%), mean:- 0.08(0.17%), SD:4.3(8.9%). Δgrip: 569 timepoints over 0.9–98.1months (median:29.7). Δright grip median:- 1kPa(-0.11%), mean:-0.87(-0.96%), SD:5.34(5.9%). Δleft median:0kPa(0%), mean:-0.82(-0.91%), SD:5.70(6.3%).

ΔMRC-SS: 75 timepoints over 1.9–52.7 months (median:10.7). Median change:0(0%), mean:0.59(0.83%), SD:4.73(6.8%). Analysis on trend identification and randomness is underway.

Conclusion

Appreciation of magnitude of normal variation is clinically important. Early identification of trends will influence dosing decisions.

ryan

keh@srft.nhs.uk|ABN Bursary

95
143  Is it ‘CLIPPERS’? Is it CNS Hemophagocytic Lymphohistiocytosis (HLH)?
Authors: Parida Amitav , Hemingway Cheryl , Eleftheriou Despina , Wassmer Evangeline
Published: May 2022

Objective

We aim to share our experiences with an Adult Neurology audience of five children (3F, 2M) with Hemophagocytic Lymphohistiocytosis (HLH), who presented with an atypical neuroinflammatory disorder.

Methods

Single institution retrospective case series

Results

Mean age of presentation was 6 years (3–11). Presenting features were headache (N=1), optic neuritis (N=1), diplopia (N=2) and hemiplegia (N=1).

4 children had MRI imaging suggestive of demyelination. One child had an isolated area of restricted diffusion in the brainstem. An initial working diagnosis of ‘CLIPPERS’ (Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) was made in three cases. Only two children ever met the criteria for systemic HLH. Pathogenic variants of RAB27A, STXBP2, UNC13 and PRF1 were separately identified in four children which are all associated with familial Hemophagocytic Lymphohis- tiocytosis (fHLH). Four children in this series have already undergone successful Haemopoietic Stem Cell Transplantation (HSCT).

Conclusions

We propose that adult neurologists consider genetic panel and immunological (Natural Killer Cell function, perforin expression and granulocyte release assay) testing for HLH in cases of atypical recurrent CNS inflammation and presentations consistent with ‘CLIPPERS’. Clinical management may be changed as HSCT is considered the gold standard treatment for familial HLH. Nonetheless, the long term history of these cases and risk of recurrent CNS inflammation post HSCT remains unclear.

a.parida@nhs.net
Ten years of monoclonals in MS have not made an obvious dent in disability progression
Authors: Allen Christopher Martin , Almulaifi Mariam , Balaska Effrosyni , Fleck Catherine , Halsey Lloyd , Tallantyre Emma , Evangelou Nikos
Published: May 2022

We audited the clinical characteristics of 327 patients with MS and clinical onset with either a transverse myelitis (TM) or optic neuritis (ON) at our two MS specialist centres. We compared those diagnosed in 2000–2010 and 2010–2020 to determine if MS disability progression is being altered by the use of mono- clonal disease modifying treatments. Our hypothesis was that TM onset disease might no longer carry a worse clinical prognosis.

More patients are being treated with monoclonals first line in the last decade (TM 12% to 27%, ON 7% to 11%). The time to MS diagnosis is shorter (5 months for TM and 25 months for ON), as was the time to treatment (4 years for both TM and ON). Contrary to our expectations, patients presenting with ON or TM during 2010–20 did not have a reduced risk of reaching EDSS 4.0. In fact, those with TM onset MS diagnosed in the last decade performed the worst overall, with 50% of the cohort reaching EDSS 4.0 within four years. Our study suggests that the effect of monoclonals is not as positive as widely assumed and pragmatic randomised trials are needed to test their real value in clinical practice.

christopher.allen@nottingham.ac.uk
011  UK variance in DMT advice and prescribing in MS and pregnancy
Authors: Dobson Ruth , Hughes Stella , Ford Helen , Murray Katy , Pearson Owen , Brex Peter , Rog David
Published: May 2022

Background

There 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.

Methods

An online questionnaire was cascaded to UK MS neurologists. Individuals completed the ques- tionnaire anonymously.

Results

85 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.

Conclusions

There 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
019  Autologous stem cell transplantation versus alemtuzumab or ocrelizumab in relapsing remitting multiple sclerosis (StarMS)
Authors: Sharrack Basil , Snowden John , Muraro Paolo
Published: May 2022

In recent years, autologous haematopoietic stem cell transplantation (aHSCT) has been increasingly used to treat patients with highly-active relapsing remitting multiple sclerosis (RRMS). Observational and limited clinical trial data suggest that aHSCT reduces relapse rates, improves disability and enhances quality of life to a greater degree than most disease modifying therapies (DMTs). There is now a need to compare aHSCT with the two most efficacious DMTs: Alemtuzumab and Ocrelizumab.

StarMS aims to determine whether aHSCT has superior clinical efficacy to Alemtuzumab and Ocreli- zumab with an acceptable safety profile. Mechanistic studies will assess immune re-constitution which will enhance understanding of the biological mechanisms of these treatments. Other sub-studies will assess their effect on cognitive recovery, neurofilament light and retinal nerve fibre layer measurements as markers of neuronal damage, and the safety of re-vaccination post-aHSCT.

This EME funded parallel-group rater-blinded RCT will randomise 198 patients (1:1) to aHSCT versus DMT (Alemtuzumab or Ocrelizumab) from 19 centres across the UK. The primary endpoint, NEDA rate, will be assessed throughout the 2-year follow-up period.

The StarMS trial has the potential to provide definitive data on the comparative efficacy of aHSCT vs highly efficacious DMTs, help improve patient outcomes, and impact national and international guidelines.

basil.sharrack@nhs.net
029  The evaluation of pain and pain management in patients with multiple sclerosis
Authors: Wallace Victoria , Cotterell Sophia , Nicholas Zara , Blain Camilla
Published: May 2022

Pain has been reported in 50–75% of people with MS. Pain is poorly understood and poorly managed impacting greatly on quality of life. Further information is required to aid better clinical recognition and management. The goal of this study was to explore the incidence, nature and management of pain in patients attending specialist MS clinic.

Methods/Results

Data was obtained using The Brief Pain Inventory and Pain Detect questionnaires and clinic letters were reviewed. 63% of MS patients reported pain. Pain was on average 6/10 at worst and 2/10 at best. 30% used simple analgesia, 43% used prescription analgesia with 56% pain relief at best. Pain interfered with activity levels, mood, sleep, relationships, and enjoyment of life. 26% had neuropathic pain and 35% had non-neuropathic pain. Pain was mentioned in 56% of clinic letters for those reporting pain. 36% had a pain management plan documented.

Conclusion

Pain is a prevalent symptom associated with MS that interferes significantly with quality of life. Pain was not always adequately or accurately addressed in MS clinic. To improve management, we suggest pain questionnaires &/or Apps are used to provide ongoing objective pain measures.

vcjwallace@gmail.com
030  Hepatitis C reactivation with fingolimod treatment for relapsing-remitting multiple sclerosis (RRMS)
Authors: Aslanyan Aram , Vilar Javier , Das Joyutpal , Mihalova Tatiana
Published: May 2022

39-year old female with RRMS switched treatment from Copaxone to Fingolimod due to clinical and radiological disease progression. After 3 years on Fingolimod treatment routine blood moni- toring identified deranged liver function tests (LFT). Additional investigation found positive Hepatitis C virus(HCV) serology, genotype 3, with 270,000 copies. Viral tests for HIV, VZV, HBV, EBV, CMV and autoimmune screening were normal. There were no risk factors for contracting Hepatitis C whilst on MS disease modifying therapy. She had blood transfusion at the age 11 and an intramuscular pain relief when examined in Turkish hospital, 1997. Stable partner of 20 years tested negative for HCV. We describe a case of latent Hepatitis C reactivation secondary to prolonged immunosuppression. Although the increased risks of herpetic viruses’ reactivation with Fingolimod are known, latent HCV reac- tivation is rather unique. Tagawa et al. described Hepatitis C virus reactivation in MS patient with known HCV positivity and undetectable HCV RNA for 4 years prior to Fingolimod exposure. Treatment guidelines do not require viral hepatitis screening prior to Fingolimod therapy. We would like to raise awareness of rare but serious complication of immunosuppressive therapy, hoping to accomplish more extensive viral screening prior to Fingolimod treatment and improve patients’ safety.

aram.aslanyan@srft.nhs.uk
032  Systematic review of prediction models in relapsing remitting multiple sclerosis
Authors: Brown Fraser , Kearns Patrick , Glasmacher Stella , Hunt David , Connick Peter , Chandran Siddharthan
Published: May 2022

Background

Prediction of individual disease course in relapsing remitting multiple sclerosis (RRMS) is chal- lenging. This has important implications for informed decision making in clinical practice.

Objectives

To conduct a systematic review in order to establish methodological quality of published prediction models in RRMS.

Methods

We searched Medline, Embase and Web of Science. Reviewers screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for adults with RRMS were included. Data collection was guided by checklist for critical appraisal and data extraction for systematic reviews and applicability and methodological quality assessment by prediction model risk of bias assessment tool.

Results

30 studies were included. Applicability was assessed as high risk of concern in 29 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n=11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation. None included impact analysis.

Conclusions

Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application in clinical practice.

fraser@tonnard.co.uk
033  Ocrelizumab: serum Ig levels and serious infections
Authors: Schmierer Klaus , Bar-Or Amit , Bermel Robert , Weber Martin S , Hughes Richard , Lin Chien-Ju , Wang Jian- mei , Craviero Licinio , Hauser Stephen L , Derfuss Tobias
Published: May 2022

Background

An apparent association between decreased Ig levels and serious infections (SIs) was pre- viously reported. Here, we characterised the temporal evolution of Ig levels and risk of SIs by baseline Ig quartile over 6 years in OPERA I/II (NCT01247324/NCT01412333), ORATORIO (NCT01194570), and their open-label extensions.

Methods

Serum Ig levels were measured ≥24 weeks. Baseline IgG/IgM/IgA quartiles (g/L) were determined; Q1 represents the lowest quartile. Changes in Ig levels and SI rates by baseline quartiles were assessed.

Results

Over 6 years, mean change in IgG levels, g/L (% change) per year by quartile were: Q1, -0.24 (-2.9%); Q2, -0.32 (-3.2%); Q3, -0.40 (-3.6%); Q4, -0.40 (-3.0%) in OPERA, and Q1, -0.23 (-2.9%); Q2, -0.28 (-2.9%);

Q3 -0.35 (-3.1%); Q4, -0.51 (-3.8%) in ORATORIO. SI rates/100PY (95% CI) were: Q1, 1.63 (0.95–2.61); Q2, 1.55

(0.90–2.48); Q3, 1.51 (0.86–2.45); Q4, 1.11 (0.57–1.94) in OPERA, and Q1, 4.04 (2.66–5.87); Q2, 3.81 (2.46–

5.62); Q3, 5.39 (3.76–7.50); Q4, 2.17 (1.22–3.59) in ORATORIO. Changes in IgM/IgA will also be presented.

Conclusions

Patients with lower baseline IgG demonstrated less absolute IgG decline, but similar per- centage decline, versus patients with higher baseline IgG. SI rates were low, and similar across quartiles.

k.schmierer@qmul.ac.uk
036  Ocrelizumab real-world effectiveness in patients with relapsing and primary progressive multiple sclerosis: MuSicalE baseline data
Authors: Hobart Jeremy , Pesch Vincent van , Rovira Alex , Alroughani Raed , Cutter Gary , Craveiro Licinio , Dzhenkova Dima , Kuenzel Thomas , Kantaria Rakesh , Trojano Maria
Published: May 2022

Background

MuSicalE (NCT03593590) is an ongoing, observational study assessing ocrelizumab effec- tiveness/safety in patients with relapsing or primary progressive multiple sclerosis (MS) treated with ocre- lizumab in routine care.

Methods

Patients with relapsing-remitting MS (RRMS), relapsing secondary progressive MS (rSPMS) or primary progressive MS (PPMS) initiating ocrelizumab per local label/guidelines are included. The primary endpoint is change in SymptoMScreen score (measures 12 common MS symptoms [range, 0–6]; higher scores indicate greater impairment).

Results

As of 5 August 2019, 324 patients were eligible for analyses. Overall, patients with rSPMS (n=25) had a longer mean disease duration (16.7 years) versus patients with RRMS (8.6 years; n=243) or PPMS (9.2 years; n=54). Mean [SD] baseline Expanded Disability Status Scale score was higher in patients with rSPMS (5.2 [1.7]) or PPMS (5.0 [1.5]), versus RRMS (3.3 [1.7]). Baseline mean (SD) total SymptoMScreen scores in patients with RRMS, rSPMS and PPMS were 23.0 (13.3), 26.8 (11.9) and 28.7 (11.2), respectively. UK-specific baseline data, including other patient-reported outcomes from secondary end points, will also be presented.

Conclusions

Baseline demographics and disease characteristics show expected differences in relapsing and progressive patients. MuSicalE will inform the real-world effectiveness/safety of ocrelizumab in a broad MS population. Recruitment is ongoing.

jeremy.hobart@plymouth.ac.uk
039  Disease modifying treatments and cancer monitoring in MS; the need for a nation-wide disease registry
Authors: Das Joyutpal , Warrens Hilary , Aslanyan Aram , Mihalova Tatiana
Published: May 2022

The immune system is inextricably linked to both cancer and Multiple Sclerosis (MS). National population- based cohort studies in Denmark and Norway have attempted to elucidate the relationship between cancer and MS, but results are conflicting. The advent of highly-efficacious disease modifying treatments (DMTs) in recent years revolutionised MS treatment, but the effect of their immunomodulating mechanism on cancer risk is unclear. Studies thus far have been limited by lack of cancer risk factor data and statistical power. In this pilot study, we identified the relevant data, including patient and cancer characteristics, DMT use, and important risk factors that may confound treatment effects. These data was collected for MS patients with cancer under the care of Salford Royal Foundation Trust. This highlighted the incomplete- ness of records, and the need for a framework for data collection. Moreover, data collection relied on multiple sources. Integration of the resultant question proforma into patient records will be a simple tool to enable reliable, homogeneous data collection. Deepening understanding of the effect of DMTs on cancer risk will improve risk-benefit treatment analysis in MS, thus improving care. Indeed, the institution of a nation-wide patient registry for such data in the UK will facilitate necessary future research.

j.das@doctors.org.uk
Unique inflammatory transcriptional profiles distinguish between sALS cases of long and short disease duration
Authors: Elliott Elizabeth , Gregory Jenna M , Dando Owen , McDade Karina , Smith Colin , Chandran Siddharthan
Published: May 2022

Amyotrophic Lateral Sclerosis (ALS) is incurable, progressively fatal and a highly heterogeneous neuro- degenerative disease. Significant variation exists across the phenotypic presentation and genetic back- ground of the condition. The identification of TDP-43 protein aggregates as a pathological hallmark of ALS has established the condition as a proteinopathy. As TDP-43 is ubiquitously expressed and regulates transcription and splicing, understanding the transcriptional profiles associated with distinct ALS clinical phenotypes, particularly those associated with neuro-resilience, is a critical yet understudied area. We carried out transcriptional profiling on motor cortex samples from a cohort of sporadic ALS cases to determine the transcriptional signatures associated with long and short disease duration. Bioinformatic gene ontology analyses identified unique inflammatory transcriptional profiles associated with these extreme disease phenotypes. Our data demonstrate that inflammatory pathway dysregulation can dis- tinguish between phenotypic extremes in ALS. Characterising the molecular profile of clinically heteroge- neous cases provides vital insight in to the underlying pathophysiology of the condition. Understanding the molecular basis of factors which confer neuro-resilience will facilitate the development of targeted disease therapies. The ability to distinguish between molecular subtypes of ALS will enable the stratifica- tion of future trials to test these therapies and also to advance disease prognostication. 17

e.elliott@ed.ac.uk
042  Determinants of baseline disability in relapsing remitting multiple sclerosis
Authors: Brown Fraser , Kearns Patrick , Martin Sarah-Jane , Connick Peter , Hunt David , Chandran Siddharthan
Published: May 2022

Background

Determinants of multiple sclerosis aetiology and natural history remain unknown.

Objectives

To determine factors associated with level of disability measured by Expanded Disability Severity Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS).

Methods

We collected demographic, clinical, smoking and alcohol history in an incidence cohort of patients with RRMS recruited within six months of diagnosis. Ordinal logistic regression was used to examine association of EDSS with clinical and demographic features. Linear regression was used to examine asso- ciation between the same variables and MSFC.

Results

We recruited 440 patients. Mean age at onset was 33.61 and 75.9% were female. Age at onset was shown to be associated with higher disability as measured by EDSS and MSFC. Sex was not signifi- cantly associated with outcome. After adjustment for age and sex, time to diagnosis, current smoking, having ever smoked and obesity were associated with higher EDSS whereas having ever smoked were associated with worse MSFC scores.

Conclusions

Disability in relapsing-remitting multiple sclerosis is partly determined by demographic features and modifiable risk factors even early in disease course. Much of the variation remains to be elucidated and individualised risk prediction is an unmet need.

fraser@tonnard.co.uk
043  Efficacy of siponimod in secondary progressive multiple sclerosis with active disease: EXPAND study subgroup analysis
Authors: Gold Ralf , Kappos Ludwig , Bar-Or Amit , Vermersch Patrick , Giovannoni Gavin , Fox Robert J , Rouyrre Nicolas , Karlsson Goril , Cree Bruce AC
Published: May 2022

Background

Siponimod, a selective sphingosine 1-phosphate receptor modulator, demonstrated clini- cally relevant effects in a typical secondary progressive multiple sclerosis (SPMS) population in the Phase 3 EXPAND study, with 21% and 26% reductions in 3- and 6-month confirmed disability progression (CDP) versus placebo.

Methods

Post hoc subgroup analysis was performed in patients with active disease (defined as the presence of relapses in 2 years before screening and/or ≥1 T1 gadolinium-enhancing [Gd ] lesion at baseline) to assess the efficacy of siponimod 2mg versus placebo in this population.Results

This analysis included 779 SPMS patients with active disease (siponimod [n=516], placebo [n=263]). The proportion of patients with relapse in the 2 years prior to study was 76% and with Gd lesions at baseline 45%. Siponimod significantly reduced 3-month CDP risk by 31% (HR [95% CI]: 0.69 [0.53, 0.91]; p=0.0094) and 6-month CDP risk by 37% (HR [95% CI]: 0.63 [0.47, 0.86], p=0.0040) versus placebo. Reductions in risk of 6 month SDMT worsening, ARR, and MRI endpoints were also seen.

Conclusions

In this subgroup of active SPMS patients from EXPAND, benefits on disability progression were more pronounced with clinically relevant effects across disability progression, cognitive processing speed, and MRI inflammatory disease activity.

g.giovannoni@qmul.ac.uk
047  Multiple sclerosis patient perspectives: disease education and communication needs
Authors: O’Neill Jessica , Ayer Mavis , Colhoun Samantha , Daykin Nicola , Hamill Brenda , Gabriele Simone , Florio Jordanne , Pulcini Serena , Thomson Alison
Published: May 2022

MS is a progressive disease that significantly impacts quality-of-life (QoL).This study aimed to identify unmet disease education and communication needs in people with MS (pwMS) to empower informed decisions, enable self-management and to maintain independence for as long as possible. A Steering Group of MS nurses and patient representatives formed and two studies for pwMS were co-developed: a qualitative Online Patient Community activity (using Ipsos’ Syndicated MS Online Patient Community) and a quantitative online survey (via the MS Trust). Data were analyzed from 28 and 117 respondents with relapsing remitting MS (RRMS), from the Ipsos’ Syndicated MS Online Patient Community and quantitative survey, respectively. Data from the quantitative survey revealed: 50% reported knowing a ‘great deal’ or a ‘fair amount’ about disability progression. Maintaining independence was a key goal for pwMS, however only 33% reported they felt that they could ‘plan for the long term’, and 21% said they set goals for managing their MS. Data from this study will explore the relationship between perceived knowledge, planning for the future, and impact on QoL. This study highlights the importance of understanding unmet needs in education, linking disease progression and impact on future QoL in pwMS.

Acknowledgements: This project was sponsored by Roche Products Ltd. Ipsos MORI UK Ltd provided support in developing and conducting the surveys and performing data analysis, which was funded by Roche Products Ltd.

jessica.oneill.jo1@roche.com
048  Postprandial somnolence in people with multiple sclerosis
Authors: Christmas Tatiana , Singh Neena , Reyes Saul , Allen-Philbey Kimberley , Giovannoni Gavin
Published: May 2022

Objectives

To identify whether people with MS (pwMS) suffer from postprandial somnolence (PPS) more than people without MS (controls), to examine whether the severity of MS is correlated to the severity of PPS and to describe strategies pwMS are using to reduce their symptoms of PPS.

Background

pwMS might be more sensitive to PPS, but no studies confirming this association have been published.

Methods

A cross-sectional study was conducted among pwMS at The Royal London Hospital, London. Patients and controls completed an online survey including demographics, comorbidities and Stanford Sleepiness Score (SSS) one hour after lunch.

Results

Survey responses of 77 pwMS (mean age 45.3 ± 11.5 years; 62.3% female) and 37 controls (mean age 47.02 ± 13.9 years; 63.8% female) were obtained. The mean SSS for pwMS was 3.46 ± 1.67, whilst the mean SSS for controls was 2.52 ± 1.18 (p=0.001). No linear correlation was observed between EDSS and SSS (R2=0.011). 63% of pwMS reported making self-administered changes to their diet to help their symptoms.

Conclusions

PwMS were affected by PPS more than controls. EDSS was not predictive of PPS severity in pwMS. pwMS are adopting self-management strategies to reduce their symptoms of PPS.

tatiana.christmas@nhs.net
050  Late onset recurrent neutropenia following ocrelizumab therapy in multiple sclerosis
Authors: Talaei Maryam , Ingram Gillian , Petheram Kate , Pearson Owen R
Published: May 2022

Ocrelizumab, an anti-CD20 monoclonal antibody similar to rituximab, has demonstrated efficacy in relapsing(RR) and primary progressive MS. Late onset neutropenia (LON) is a rare side-effect of rituximab and there only 2 cases reported related to ocrelizumab. We discuss 2 treatment naive patients with active RRMS who developed LON after ocrelizumab treatment.

A 31y female presented with neutropenic sepsis 115 days after third ocrelizumab infusion, requiring treatment with intravenous antibiotics and granulocyte colony stimulating factor (G-CSF). Subsequent multiple episodes of recurrent grade 4 neutropenia occurred over the next 6 months, often requiring G-CSF treatment. Bone marrow aspiration demonstrated normocellular granulopoiesis.

A 35y male developed neutropenic sepsis 119 days after first ocrelizumab infusion which recovered rapidly with G-CSF. He received the second dose of ocrelizumab 3 months later, and at 5 months follow up after his third infusion had no recurrent neutropenia.

The two cases demonstrate the spectrum of late onset neutropeniaof LON with oOcrelizumab. The aetiology of LON is poorly understood but hypothesised to be autoimmune in nature. The cases are important to raise the clinical suspicion of this life threatening complication of disease modifying therapy. Further experience is required to understand risk of recurrence and when to re-challenge with ocrelizumab.

maryam.talaei@wales.nhs.uk