Publications by authors named "Alasdair Coles"

113 Publications

The MS Remyelinating Drug Bexarotene (an RXR Agonist) Promotes Induction of Human Tregs and Suppresses Th17 Differentiation .

Front Immunol 2021 10;12:712241. Epub 2021 Aug 10.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

The retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (RA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of RA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.
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http://dx.doi.org/10.3389/fimmu.2021.712241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382874PMC
August 2021

Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study.

Lancet Neurol 2021 09;20(9):709-720

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis.

Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed.

Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55).

Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies.

Funding: Multiple Sclerosis Society of the United Kingdom.
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http://dx.doi.org/10.1016/S1474-4422(21)00179-4DOI Listing
September 2021

Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury.

J Immunol 2021 Jun 18. Epub 2021 Jun 18.

Department of Clinical Neurosciences, University of Cambridge, United Kingdom.

Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.
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http://dx.doi.org/10.4049/jimmunol.2001309DOI Listing
June 2021

Deciphering neurological symptoms in ANCA-associated vasculitis, uncontrolled disease or a complication of therapy.

Rheumatology (Oxford) 2021 06;60(Suppl 3):iii67-iii69

Vasculitis and Lupus Clinic, Department of Medicine, Cambridge University Hospital, Cambridge, UK.

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http://dx.doi.org/10.1093/rheumatology/keab103DOI Listing
June 2021

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial.

Ther Adv Neurol Disord 2021 23;14:1756286420982134. Epub 2021 Apr 23.

Department of Neurology, University of Warmia and Mazury, Olsztyn, Poland.

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline.

Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab.

Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups.

Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups.

Clinicaltrialsgov Identifiers: NCT00530348; NCT00548405; NCT00930553.
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http://dx.doi.org/10.1177/1756286420982134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072102PMC
April 2021

Use of Disease-Modifying Therapies in Pediatric Relapsing-Remitting Multiple Sclerosis in the United Kingdom.

Neurol Neuroimmunol Neuroinflamm 2021 07 21;8(4). Epub 2021 May 21.

From the Queen Square MS Centre (O.A.A., W.B., O.C., C.H., Y.H.), UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London; Department of Neurology (O.A.A., O.C., C.H., Y.H.), Great Ormond Street Hospital for Children, London; Children's Neurosciences (C.M.), Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation; Department of Paediatric Neurology (T.R., M.C.), Addenbrooke's Hospital, Cambridge; Department of Neurology (J.-C.S., R.K.), Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom; Queen Square Institute of Neurology (C.T.), Faculty of Brain Sciences, University College London; Multiple Sclerosis Centre of Catalonia (Cemcat) (C.T.), Vall d'Hebron Institute of Research, Vall d'Hebron Barcelona Hospital Campus, Spain; Children's Neurosciences (S.B.), Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London; Department of Clinical Neurosciences (A.C.), Addenbrooke's Hospital, Cambridge; Translational and Clinical Research Institute (R.F.), Newcastle University; Department of Neuroradiology (K.M.), Great Ormond Street Hospital for Children, London; Department of Neurology (D.R., S. West), Royal Manchester Children's Hospital, Manchester; Department of Neurology (S. Wright, E.W.), Birmingham Children's Hospital, Birmingham; Aston Neuroscience Institute (S. Wright, E.W.), College of Health and Life Sciences, Aston University, Birmingham, United Kingdom; Evelina London Children's Hospital (M.L.), Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, United Kingdom; and NIHR University College London Hospitals Biomedical Research Centre (O.C.).

Objectives: To compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS).

Methods: In this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records. Annualized relapse rates (ARRs) before and on treatment, time to relapse, time to new MRI lesions, and change in Expanded Disability Status Scale (EDSS) score were calculated.

Results: Of 103 children treated with DMTs, followed up for 3.8 years, relapses on treatment were recorded in 53/89 (59.5%) on injectables vs 8/54 (15%) on newer DMTs. The ARR was reduced from 1.9 to 1.1 on injectables ( < 0.001) vs 1.6 to 0.3 on newer DMTs ( = 0.002). New MRI lesions occurred in 77/89 (86.5%) of patients on injectables vs 26/54 (47%) on newer DMTs ( = 0.0001). Children on newer DMTs showed longer time to relapse, time to switch treatment, and time to new radiologic activity than patients on injectables (log-rank < 0.01). After adjustment for potential confounders, multivariable analysis showed that injectables were associated with 12-fold increased risk of clinical relapse (adjusted hazard ratio [HR] = 12.12, 95% CI = 1.64-89.87, = 0.015) and a 2-fold increased risk of new radiologic activity (adjusted HR = 2.78, 95% CI = 1.08-7.13, = 0.034) compared with newer DMTs. At 2 years from treatment initiation, 38/103 (37%) patients had MRI activity in the absence of clinical relapses. The EDSS score did not change during the follow-up, and only 2 patients had cognitive impairment.

Conclusion: Newer DMTs were associated with a lower risk of clinical and radiologic relapses in patients compared with injectables. Our study adds weight to the argument for an imminent shift in practice toward the use of newer, more efficacious DMTs in the first instance.

Classification Of Evidence: This study provides Class IV evidence that newer DMTs (oral or infusions) are superior to injectables (interferon beta/glatiramer acetate) in reducing both clinical relapses and radiologic activity in children with RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000001008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143699PMC
July 2021

COVID-19 is associated with new symptoms of multiple sclerosis that are prevented by disease modifying therapies.

Mult Scler Relat Disord 2021 Jul 5;52:102939. Epub 2021 May 5.

Mental Health and Clinical Neuroscience Academic Unit, School of Medicine, University of Nottingham, Nottingham, UK; Clinical Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK. Electronic address:

Background: Infections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS.

Methods: The COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms.

Results: Fifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection.

Conclusion: COVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.
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http://dx.doi.org/10.1016/j.msard.2021.102939DOI Listing
July 2021

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 Jan 11:1352458520981300. Epub 2021 Jan 11.

CHU de Caen, MS Expert Centre, Department of Neurology, avenue de la Côte-de-Nacre, Normandy University, Caen, France.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups.

Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation.

Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants.

Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5).

Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
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http://dx.doi.org/10.1177/1352458520981300DOI Listing
January 2021

Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis.

J Neurol Neurosurg Psychiatry 2021 03 12;92(3):295-302. Epub 2020 Nov 12.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Objective: To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS).

Methods: We long-listed licensed drugs with evidence of human safety, blood-brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review.

Results: From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine.

Conclusions: We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.
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http://dx.doi.org/10.1136/jnnp-2020-324286DOI Listing
March 2021

Delay from treatment start to full effect of immunotherapies for multiple sclerosis.

Brain 2020 09;143(9):2742-2756

Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, 34142, Turkey.

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
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http://dx.doi.org/10.1093/brain/awaa231DOI Listing
September 2020

Guidelines on the use of irradiated blood components.

Br J Haematol 2020 12 18;191(5):704-724. Epub 2020 Aug 18.

Department of Clinical Nephrology and Transplantation, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

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http://dx.doi.org/10.1111/bjh.17015DOI Listing
December 2020

GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop.

J Parkinsons Dis 2020 ;10(3):875-891

The Cure Parkinson's Trust, London, UK.

The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
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http://dx.doi.org/10.3233/JPD-202004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458523PMC
August 2021

Clinical features and genetic risk of demyelination following anti-TNF treatment.

J Crohns Colitis 2020 Jun 4. Epub 2020 Jun 4.

IBD Pharmacogenetics Group, University of Exeter, Exeter, UK.

Background: Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and test whether affected patients were genetically predisposed to multiple sclerosis (MS).

Methods: We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF. We compared genetic risk scores (GRS), calculated using carriage of 43 susceptibility loci for MS, in 48 cases to 1219 patients exposed to anti-TNF who did not develop demyelination.

Results: Overall, 39 (74%) cases were female. The median age (range) of patients at time of demyelination was 41.5 years (20.7 - 63.2). The median duration of anti-TNF treatment was 21.3 months (0.5 - 99.4) and 19 (36%) patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord or both. Complete recovery was reported in 12 (23%) patients after a median time of 6.8 months (0.1 - 28.7). After 33.0 months of follow-up partial recovery was observed in 29 (55%) patients, relapsing and remitting episodes in 9 (17%), progressive symptoms in 3 (6%): 2 (4%) patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 x 10-4, SD 0.0039) and controls (mean -1.1×10-3, SD 0.0042) (p=0.23).

Conclusions: Patients who experienced demyelination events following anti-TNF were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa104DOI Listing
June 2020

Neurological Implications of COVID-19 Infections.

Neurocrit Care 2020 06;32(3):667-671

Division of Anaesthesia, University of Cambridge, Cambridge, UK.

The magnitude of the COVID-19 pandemic will result in substantial neurological disease, whether through direct infection (rare), para-infectious complications (less rare), or critical illness more generally (common). Here, we raise the importance of stringent diagnosis and data collection regarding neurological complications of COVID-19; we urge caution in the over-diagnosis of neurological disease where it does not exist, but equally strongly encourage the concerted surveillance for such conditions. Additional to the direct neurological complications of COVID-19 infection, neurological patients are at risk of harm from both structural limitations (such as number of intensive care beds), and a hesitancy to treat with certain necessary medications given risk of nosocomial COVID-19 infection. We therefore also outline the specific management of patients with neuroinflammatory diseases in the context of the pandemic. This article describes the implications of COVID-19 on neurological disease and advertises the Neurocritical Care Society's international data collection collaborative that seeks to align data elements.
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http://dx.doi.org/10.1007/s12028-020-00978-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188454PMC
June 2020

Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol.

Contemp Clin Trials 2020 08 19;95:106009. Epub 2020 Apr 19.

Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom.

Multiple Sclerosis (MS) is a common cause of neurological disability among young adults and has a high economic burden. Currently there are 18 disease modifying agents for relapsing MS, which were tested in clinical trials versus placebo or an active comparator in a pairwise manner. However, there is currently no consensus on the fundamental principles of treatment approach and initial therapy selection. These factors result in variable use of disease modifying therapies. Here we describe the study protocol for Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the Treatment of Relapsing-remitting Multiple Sclerosis (DELIVER-MS). The main objective of the study is to determine whether an early highly effective treatment approach, defined as use of one of four monoclonal antibodies as initial therapy, is more effective than an escalation treatment approach (any other approved medication as initial therapy with subsequent escalation to higher efficacy treatments guided by radiological and clinical evaluation). The primary endpoint of the study is reduction in normalized brain volume loss from baseline visit to month 36 visit using MRI. Brain volume loss was selected as the best short-term predictor of long-term clinical disability. A total of 400 participants will be randomized 1:1 using minimization to account for age and sex by site, and 400 will be enrolled into a parallel observational cohort. The study results will help guide overall treatment philosophy and will have important implications for patient choice, clinical practice, and treatment access.
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http://dx.doi.org/10.1016/j.cct.2020.106009DOI Listing
August 2020

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.

Lancet Neurol 2020 04 18;19(4):307-316. Epub 2020 Mar 18.

School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland; St Vincent's University Hospital, Dublin, Ireland.

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset.

Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model.

Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period.

Interpretation: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.

Funding: National Health and Medical Research Council Australia and MS Society UK.
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http://dx.doi.org/10.1016/S1474-4422(20)30067-3DOI Listing
April 2020

Hyperpolarized C MRI: A novel approach for probing cerebral metabolism in health and neurological disease.

J Cereb Blood Flow Metab 2020 06 10;40(6):1137-1147. Epub 2020 Mar 10.

Department of Radiology, University of Cambridge, Cambridge, UK.

Cerebral metabolism is tightly regulated and fundamental for healthy neurological function. There is increasing evidence that alterations in this metabolism may be a precursor and early biomarker of later stage disease processes. Proton magnetic resonance spectroscopy (H-MRS) is a powerful tool to non-invasively assess tissue metabolites and has many applications for studying the normal and diseased brain. However, the technique has limitations including low spatial and temporal resolution, difficulties in discriminating overlapping peaks, and challenges in assessing metabolic flux rather than steady-state concentrations. Hyperpolarized carbon-13 magnetic resonance imaging is an emerging clinical technique that may overcome some of these spatial and temporal limitations, providing novel insights into neurometabolism in both health and in pathological processes such as glioma, stroke and multiple sclerosis. This review will explore the growing body of pre-clinical data that demonstrates a potential role for the technique in assessing metabolism in the central nervous system. There are now a number of clinical studies being undertaken in this area and this review will present the emerging clinical data as well as the potential future applications of hyperpolarized C magnetic resonance imaging in the brain, in both clinical and pre-clinical studies.
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http://dx.doi.org/10.1177/0271678X20909045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238376PMC
June 2020

Parkinson's disease and spirituality.

NeuroRehabilitation 2020 ;46(1):31-39

Faraday Institute for Science and Religion, Cambridge, UK.

Objective: To assess the claim that Parkinson's disease (PD) specifically reduces religiosity religious faith and spirituality.

Methods: A longitudinal case-control study over 12 months of spirituality in 42 patients with idiopathic PD and 39 disease controls matched for age, gender, educational attainment and disability. There was no selection on grounds of religious affiliation. Participants were assessed on the Beck Depression Inventory, Medical Outcomes Score (MOS), cognitive tests including Paired Associate Learning [PAL], One Touch Stocking [OTS]) and Stroop test. Tests of spirituality were the Brief Multidimensional Measure of Religiousness and Spirituality questionnaire (BMMRS), a Mystical Experiences Questionnaire (MEQ), and the Rivermead Life Goals Score, supplemented by qualitative interview methods.

Results: Over one year, as expected, mobility and cognition declined in the PD group. However, there was no significant change in scores of religiosity and spirituality scores in this group. Likewise, there were no subjective reports of a decrease of interest in religious faith or spirituality, although anecdotal accounts of decreasing mobility, loss of driving ability, increasing emotional lability and tiredness meant reduced participation in some religious and spiritual practices. However, over one year there was a significant fall in controls' religiosity score due mainly to a fall in 'religious practices' with no clear underlying reason.

Conclusions: Compared to non-neurological patients with similar disability, Parkinson's disease is not associated with a decline in religious faith or spirituality. Declining mobility and cognition in Parkinson's disease does not lead to diminished religiosity.
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http://dx.doi.org/10.3233/NRE-192947DOI Listing
July 2020

Transcript specific regulation of expression influences susceptibility to multiple sclerosis.

Eur J Hum Genet 2020 06 13;28(6):826-834. Epub 2020 Jan 13.

Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Box 165, Hills Road, Cambridge, CB2 0QQ, UK.

Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.
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http://dx.doi.org/10.1038/s41431-019-0569-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253460PMC
June 2020

Promoting remyelination in multiple sclerosis.

J Neurol 2021 Jan 12;268(1):30-44. Epub 2019 Jun 12.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

The greatest unmet need in multiple sclerosis (MS) are treatments that delay, prevent or reverse progression. One of the most tractable strategies to achieve this is to therapeutically enhance endogenous remyelination; doing so restores nerve conduction and prevents neurodegeneration. The biology of remyelination-centred on the activation, migration, proliferation and differentiation of oligodendrocyte progenitors-has been increasingly clearly defined and druggable targets have now been identified in preclinical work leading to early phase clinical trials. With some phase 2 studies reporting efficacy, the prospect of licensed remyelinating treatments in MS looks increasingly likely. However, there remain many unanswered questions and recent research has revealed a further dimension of complexity to this process that has refined our view of the barriers to remyelination in humans. In this review, we describe the process of remyelination, why this fails in MS, and the latest research that has given new insights into this process. We also discuss the translation of this research into clinical trials, highlighting the treatments that have been tested to date, and the different methods of detecting remyelination in people.
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http://dx.doi.org/10.1007/s00415-019-09421-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815564PMC
January 2021

Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2).

Trials 2019 Jun 7;20(1):331. Epub 2019 Jun 7.

Department of Clinical Neurosciences, University of Cambridge, Box 165, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.

Background: Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care.

Methods: We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2-4 consecutive days no later than 7 days from baseline. It will continue 4-5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2-3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response.

Discussion: The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies.

Trial Registration: ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.
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http://dx.doi.org/10.1186/s13063-019-3336-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555751PMC
June 2019

Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab.

Mult Scler 2020 08 6;26(9):1093-1101. Epub 2019 Jun 6.

NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK; National Institute for Health Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre, London, UK.

Background: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions.

Objective: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient's evolution, and whether baseline gradients predict on-treatment relapses.

Methods: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups' baseline gradients and evolution.

Results: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (-0.045 pu/band/year,  = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number ( = 0.568) nor brain parenchymal fraction ( = 0.187) between those who relapsed within 4 years ( = 4) and those who did not ( = 15). However, the baseline gradient was significantly different ( = 0.020).

Conclusion: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients - but not lesion loads or brain volumes - may predict on-treatment relapses. Larger confirmatory studies are required.
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http://dx.doi.org/10.1177/1352458519852093DOI Listing
August 2020

Keratinocyte growth factor impairs human thymic recovery from lymphopenia.

JCI Insight 2019 05 7;5. Epub 2019 May 7.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Background: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.

Methods: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.

Findings: At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.

Trial Registration: ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation.
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http://dx.doi.org/10.1172/jci.insight.125377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629095PMC
May 2019

Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis.

Mult Scler 2019 08 15;25(9):1273-1288. Epub 2019 Apr 15.

School of Medicine, University of Cambridge, Cambridge, UK.

Background: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population.

Objective: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients.

Methods: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use.

Results: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria.

Conclusion: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.
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http://dx.doi.org/10.1177/1352458519841829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681440PMC
August 2019

Acute posterior multifocal placoid pigment epitheliopathy after alemtuzumab treatment for relapsing-remitting multiple sclerosis.

J Neurol 2019 06 20;266(6):1539-1540. Epub 2019 Mar 20.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1007/s00415-019-09288-yDOI Listing
June 2019

A case of anaphylaxis to alemtuzumab.

J Neurol 2019 Mar 4;266(3):780-781. Epub 2019 Feb 4.

Department of Clinical Neurosciences, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

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http://dx.doi.org/10.1007/s00415-019-09214-2DOI Listing
March 2019

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

JAMA 2019 01;321(2):175-187

Department of Neurology, Southmead Hospital, and Clinical Neurosciences, University of Bristol, Bristol, United Kingdom.

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.

Design, Setting, And Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.

Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).

Main Outcome And Measure: Conversion to objectively defined secondary progressive MS.

Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).

Conclusions And Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.
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http://dx.doi.org/10.1001/jama.2018.20588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439772PMC
January 2019

Quantifying normal human brain metabolism using hyperpolarized [1-C]pyruvate and magnetic resonance imaging.

Neuroimage 2019 04 11;189:171-179. Epub 2019 Jan 11.

Department of Radiology, University of Cambridge, Cambridge, UK. Electronic address:

Hyperpolarized C Magnetic Resonance Imaging (C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the cerebral metabolism of intravenously injected hyperpolarized [1-C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of C images demonstrated C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (k) for exchange of the hyperpolarized C label between [1-C]pyruvate and the endogenous lactate pool was 0.012 ± 0.006 s and the apparent rate constant (k) for the irreversible flux of [1-C]pyruvate to [C]bicarbonate was 0.002 ± 0.002 s. Imaging also revealed that [1-C]pyruvate, [1-C]lactate and [C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1-C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.
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http://dx.doi.org/10.1016/j.neuroimage.2019.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435102PMC
April 2019

Immune reconstitution after alemtuzumab therapy for multiple sclerosis triggering Graves' orbitopathy: a case series.

Eye (Lond) 2019 02 29;33(2):223-229. Epub 2018 Nov 29.

Thyroid Eye Disease Service, Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Alemtuzumab-a monoclonal antibody targeting the CD52 glycoprotein expressed by most mature leucocytes-effectively decreases relapse rate and disability progression in early, relapsing-remitting multiple sclerosis (MS). However, secondary autoimmune disorders complicate therapy in nearly 50% of treated patients, with Graves' disease being the most common. Rarely, thyroid eye disease (TED) ensues; only seven such cases have been reported. Our aim was to analyse the largest series of MS patients developing thyroid eye disease after alemtuzumab treatment. We performed a retrospective chart review of MS patients treated with alemtuzumab (1995-2018) and subsequently identified by their treating physicians as having developed TED and referred to our ophthalmology service. As an original trial centre for alemtuzumab, our hospital has treated approximately 162 MS patients with this novel therapy. In total, 71 (44%) developed thyroid dysfunction, most of whom (87%) developed Graves' disease, with ten (16%) referred for ophthalmological evaluation. Two developed active orbitopathy following radioiodine treatment; one occurred after cessation of anti-thyroid drug treatment. Three developed sight-threatening disease requiring systemic immunosuppression, with one refractory to multiple immunosuppressants. The remaining patients were treated conservatively. TSH-receptor antibody (TRAb) levels were significantly raised in all cases, when ascertained. We report sight-threatening as well as mild TED in MS patients after treatment with alemtuzumab. Endocrine instability, radioiodine treatment and positive TRAb are all likely risk factors. The data support at least 6-monthly biochemical and clinical assessment with a low threshold for referral to an ophthalmologist, particularly for those with higher TRAb levels who may be at greater risk of orbitopathy.
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http://dx.doi.org/10.1038/s41433-018-0282-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367353PMC
February 2019
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