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J William L Brown, Alasdair J ColesDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UKAbstract: Alemtuzumab (previously known as Campath®) is a humanized monoclonal antibody directed against the CD52 antigen on mature lymphocytes that results in lymphopenia and subsequent modification of the immune repertoire. Here we explore evidence for its efficacy and safety in relapsing–remitting multiple sclerosis. One Phase II and two Phase III trials of alemtuzumab versus active comparator (interferon beta-1a) have been reported. Two of these rater-blinded randomized studies assessed clinical and radiological outcomes in treatment-naïve patients; one explored patients who had relapsed despite first-line therapy. Compared to interferon beta-1a, alemtuzumab reduced the relapse rate by 49%–74% (P < 0.0001), and in two studies it reduced the risk of sustained disability accumulation by 42%–71% (P < 0.01). In one study (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis; CARE-MS1), there was no significant difference compared to interferon, perhaps reflecting the surprisingly low frequency of disability events in the comparator group. After alemtuzumab, the Expanded Disability Status Scale score improved by 0.14–1.2 points, culminating in a net advantage with alemtuzumab of 0.41–0.77 points over interferon in the CAMMS223 and CARE-MS2 trials (both P < 0.001). Radiological markers of new lesion formation and brain atrophy following alemtuzumab were significantly improved when compared to interferon in all studies. Adverse events were more common following alemtuzumab than interferon beta-1a (7.2–8.66 versus 4.9–5.7 events per person-year). While infusion reactions are the most common, autoimmunity is the most concerning; within Phase III studies, thyroid disorders (17%–18% versus 5%–6%) and immune thrombocytopenic purpura (1% versus 0%) were reported in patients taking alemtuzumab and interferon beta-1a, respectively. All patients responded to conventional therapy. One patient taking alemtuzumab in the Phase II study suffered a fatal intracranial hemorrhage following immune thrombocytopenic purpura, heralding assiduous monitoring of all patients thereafter. Alemtuzumab has been submitted for licensing in relapsing–remitting multiple sclerosis in the United States and Europe.Keywords: alemtuzumab, Campath, efficacy, relapsing–remitting multiple sclerosis

Alemtuzumab is a humanized monoclonal antibody that is administered daily for 5 days, and then no further therapy is required for 12 months. It causes rapid and prolonged lymphocyte depletion; the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells. Although previously licensed for the treatment of B-cell chronic lymphocytic leukemia, it is now been considered for licensing in the treatment of multiple sclerosis (MS). From a disappointing experience with alemtuzumab in progressive MS, Alastair Compston and I argued that immunotherapies should be given early in the course of the disease. In a unique program of drug development in MS, alemtuzumab has been compared in 1 phase 2 trial and 2 phase 3 trials with the active comparator interferon beta-1a. In all trials, alemtuzumab was more effective in suppressing relapses than interferon beta-1a. In one phase 2 and one phase 3 trial, alemtuzumab also reduced the risk of accumulating disability compared with interferon beta-1a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy. The safety issues are infusion-associated reactions largely controlled by methylprednisolone, antihistamines, and antipyretics; mild-to-moderate infections (with 3 opportunistic infections from the open-label experience: 1 case each of spirochaetal gingivitis, pyogenic granuloma, and Listeria meningitis); and autoimmunity. Usually autoimmunity is directed against the thyroid gland, but causes (1 %) immune thrombocytopenia, and in a few cases antiglomerular basement membrane syndrome. Alemtuzumab is an effective therapy for early relapsing-remitting MS, offering disability improvement at least to 5 years after treatment. Its use requires careful monitoring so that potentially serious side effects can be treated early and effectively. [ABSTRACT FROM AUTHOR]

To save their patients from dialysis and transplantation, neurologists need simply remain alert to the possibility of renal failure, particularly in the context of systemic disease, diabetes, sepsis and drugs. Of the numerous territories shared by our respective specialities, we outline a pragmatic approach to the diagnosis and treatment of the vasculitides, underpinned by knowing which questions to ask, equally importantly when to ask them, and in the art of obtaining a tissue diagnosis. We consider the current evolving trial evidence that directs the usage of a growing arsenal of therapies in the induction and maintenance stages of vasculitis treatment, and extend this consideration to Lupus and Sjogren's. [ABSTRACT FROM AUTHOR]

The Cambridge Centre for Myelin Repair One (CCMR-One) trial showed that 6 months of bexarotene reduces visual evoked potential (VEP) latency in people with relapsing-remitting multiple sclerosis (MS). In a single-centre follow-up study of these participants, we re-examined full-field VEP and clinical assessments. Twenty participants (12 bexarotene and 8 placebo) were seen on average 27 months after their trial involvement. In an analysis of all eyes with recordable signal (24 bexarotene and 14 placebo), the adjusted bexarotene-placebo treatment difference in P100 latency was -7.79 (95% confidence interval (CI) = -14.76, -0.82) ms, p  = 0.044. We conclude that there were durable improvements in VEP latency, suggesting long-term benefits from exposure to a remyelinating drug., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: C.E.M. and T.M. have nothing to disclose. J.W.L.B. reports consulting and lecture fees from The Corpus, Biogen Idec and Novartis. A.J.C. and N.G.C. report grants from MS Society of GB, during the conduct of the study. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Background: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection., Methods: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment., Results: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups., Conclusions: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

One of the most promising approaches to delay, prevent or reverse disability progression in multiple sclerosis (MS) is to enhance endogenous remyelination and limit axonal degeneration. In clinical trials of remyelinating drugs, there is a need for reliable, sensitive and clinically relevant outcome measures. The visual pathway, which is frequently affected by MS, provides a unique model system to evaluate remyelination of acute and chronic MS lesions in vivo and non-invasively. In this review, we discuss the different measures that have been used and scrutinise visual outcome measure selection in current and future remyelination trials., Competing Interests: Competing interests: Gioia Riboni-Verri, Benson S Chen, Christopher E McMurran, Gregory J Halliwell and Nick Cunniffe declare they have no financial interests. J William L Brown received speaking fees, consulting fees and travel support from Biogen, Novartis and Roche. Alasdair J Coles received grant support, honoraria and travel support from Sanofi up until September 2017. Nil since., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS., Methods and Analysis: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs., Ethics and Dissemination: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences., Trial Registration Number: ISRCTN88667898., Competing Interests: Competing interests: GB, JP, KEMD, RG, KH, DPap, ER, CB, MG, OC, CC, GG, MK, CK, RN, DPal, AP, NS, ES, TdS, AV, SW, BS report no relevant competing interests. AC reports no relevant disclosures since 2017. RH reports attendance at paid advisory boards with Novartis, Biogen and Roche. CAY reports personal compensation for serving on scientific advisory boards, conference support or speaker honoraria from BMS, Biogen, Celgene, Cytokinetics, GW Pharmaceuticals, Novartis, Roche and Teva. Pharmaceuticals. PAM reports grants from National Institute of Health Research, non-financial support from National Institute of Health Research, grants from Benaroya Research Institute and National Institute of Allergy and Infectious Diseases of the National Institutes of Health, during the conduct of the study; personal fees from Jasper Therapeutics, personal fees from Magenta Therapeutics, personal fees from Rubius Therapeutics, outside the submitted work. JAS declares consultancy for Jazz, Medac, Vertex and Kiadis., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely., (© 2023. The Author(s).)

Background and Objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation)., Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]., Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent., Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course., Clinicaltrialsgov Identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656., Competing Interests: AJC reports consulting fees, lecture fees, and institutional grant support from Sanofi up to September 2017. AA reports research and travel grants, honoraria for MS-expert advice and consulting, and/or speaking fees (Biogen, Merck Serono, Novartis, Roche, and Sanofi). AT reports consulting and/or speaking fees and grant/research support (Biogen, EMD Serono, Novartis, Roche, and Sanofi). BAS reports research grant support from AbbVie, Biogen, Bristol Myers Squibb, Greenwich Biosciences, Novartis, and Sanofi; and consulting and/or speaking fees from AbbVie, Alexion, Biogen, Bristol Myers Squibb, Cigna, EMD Serono, Janssen, Genentech, Greenwich Biosciences, Horizon, Novartis, Octave Bioscience, Roche, Sanofi, and TG Therapeutics. CP reports consulting and/or speaking fees, research, and travel grants (Actelion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, and Teva). COG reports speaking and/or consultancy fees (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). GG reports compensation for serving as a consultant or speaker for or has received research support from AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva in the past 5 years. GC reports consulting fees (Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi, and Teva) and lecture fees (Bayer Schering, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva). MS Freedman reports honoraria/consulting fees (Alexion/AstraZeneca, Atara Biotherapeutics, Bayer HealthCare, Beigene, BMS/Celgene, EMD Inc., Hoffman La-Roche, Janssen/J&J, Merck Serono, Quanterix, Novartis, Sanofi, and Teva Canada Innovation); serving as a member of an advisory board, board of directors, or other similar group (Alexion, Atara Biotherapeutics, Bayer HealthCare, Beigene, BMS/Celgene, Celestra, Hoffman La-Roche, Janssen/J&J, McKesson, Merck Serono, Novartis and Sanofi); participation in the speakers bureau (EMD Serono and Sanofi); and grant/research support (Sanofi). TZ reports consulting and/or speaking fees (Almirall, Bayer, Biogen, BMS, Celgene, Merck, Novartis, Roche, Sanofi, Viatris and Teva) and grant/research support (Biogen, BMS, Novartis, Roche, Sanofi, and Teva). DS, AMR, ATW, and MC are employees of Sanofi and may hold shares and/or stock options in the company. XM reports speaking honoraria and travel expenses for scientific meetings, being a steering committee member of clinical trials, or participating in advisory boards of clinical trials in the past 3 years (Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, EXCEMED, MedDay, Merck, MSIF, NervGen, NMSS, Novartis, Roche, Sanofi, Teva Pharmaceutical, and TG Therapeutics)., (© The Author(s), 2023.)

Background: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear., Objective: To determine whether early non-disabling relapses predict disability accumulation in RRMS., Methods: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up., Results: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n  = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs ( n  = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs ( n  = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically., Conclusion: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

In carefully selected patients, autologous haematopoietic stem cell transplantation (HSCT) is a safe, highly effective and cost-saving treatment modality for treatment-resistant, and potentially treatment-naïve, immune-mediated neurological disorders. Although the evidence base has been growing in the last decade, limited understanding has led to confusion, mistrust and increasing use of health tourism. In this article, we discuss what autologous HSCT is, which immune-mediated conditions can be treated with it, how to select patients, what are the expected outcomes and potential adverse effects, and how cost-effective this treatment is., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid-X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age-related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Despite impressive efficacy in immunocompetent individuals, the immunogenicity of a single dose of COVID-19 vaccine in B-cell-deplete patients remains unknown., Objectives: We aimed to quantify real-world vaccine immunogenicity in ocrelizumab recipients., Methods: We measured post-vaccination SARS-COV-2 immunoglobulin G (IgG) in ocrelizumab recipients using a highly sensitive Luminex assay., Results: 44.1% of patients had detectable SARS-COV-2-IgG 21+ days after one vaccine dose, regardless of vaccine type (AZD1222 vs BNT162b2, odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.157-2.32, p = 0.72). B-cell count strongly predicted seroconversion (β1 = 12.38, 95% CI = 4.59-20.16, p = 0.0029), but undetectable B-cells did not preclude it. The second vaccine seroconverted 53% of the patients who had not already responded to dose 1., Conclusion: Humoral response after one COVID-19 vaccine dose is lower than expected in CD20-deplete patients.

The inflammatory response to acute brain injuries is a key contributor to subsequent outcome. The study of local central nervous system inflammatory responses is hindered by raised intracranial pressure precluding cerebrospinal fluid sampling by lumbar puncture. External ventricular drains are sited in some acute brain injury patients to divert cerebrospinal fluid and thus reduce intracranial pressure, and represent a potential route to safely gather large volumes of cerebrospinal fluid for immunological studies. In this manuscript we show that mononuclear cells can be isolated from cerebrospinal fluid collected from external ventricular drains, and that the large volumes of cerebrospinal fluid available yield sufficient mononuclear cells to allow cryopreservation. Prolonged storage of cerebrospinal fluid in the external ventricular drain collection bag can alter the phenotype of cells recovered, but the predicted effect of this can be estimated for a given flow cytometry panel by assessing the changes in peripheral blood mononuclear cells exposed to the same conditions. The described method will allow clinical studies of acute brain injuries to investigate the immunological processes occurring within the central nervous system compartment, rather than relying on changes in the peripheral circulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression., (© 2021. The Author(s).)

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 2 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., Competing Interests: Declaration of interests JWLB reports personal fees from Biogen for real-world evidence consultation, outside the submitted work. NGC reports grants from the Multiple Sclerosis Society of the United Kingdom, during the conduct of the study. JLJ reports grants and personal fees from Sanofi, outside the submitted work. DR reports grants from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, TG Therapeutics, and Mitsubishi, and personal fees from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, Janssen, and Celgene, outside the submitted work. ORP reports personal fees from Biogen, Genzyme, Merck, Novartis, Celegene, and Roche, outside the submitted work. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene, Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global, and Allergan, and employment from Hoffmann La-Roche, outside the submitted work, and is a shareholder of Hoffmann La-Roche. Cf-C reports grants from Roche, outside the submitted work. CM reports personal fees from Sanofi, AstraZeneca, and Apitope, and non-financial support from Sanofi and AstraZeneca, outside the submitted work. RJMF reports grants from Biogen, and personal fees from Biogen, Frequency Therapeutics, and Rewind Therapeutics, outside the submitted work. SC reports funding from Phenotherapeutics, outside the submitted work. DTC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study, and personal fees from Biogen and Hoffmann-La Roche, grants from the International Progressive MS Alliance and the Multiple Sclerosis Society of the United Kingdom, and infrastructure support from the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, outside the submitted work. AJC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 ( at RA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation in vitro. 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 at RA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive in vitro. 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gaunt, Rainbow, Mackenzie, Jarvis, Mousa, Cunniffe, Georgieva, Brown, Coles and Jones.)

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., (Copyright © 2021 by The American Association of Immunologists, Inc.)

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 versus 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 versus 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., Competing Interests: Conflict of interest statement: AJC reports receiving consulting fees, lecture fees, and institutional grant support from Sanofi prior to 2017. DLA reports receiving consulting fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Celgene, Frequency Therapeutics, Genentech, Genzyme, Hoffmann-La Roche, Immune Tolerance Network, Immunotec, MedDay, Merck Serono, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis, Canadian Institutes of Health Research, MS Society of Canada, International Progressive MS Alliance, and an equity interest in NeuroRx Research. ADB reports receiving research funding, compensation for medical advisory boards, and compensation for speakers bureaus from Actelion, Biogen, EMD Serono, Genentech-Roche, Mallinckrodt, Novartis, Sanofi, and TG Therapeutics. ALB reports receiving consulting fees and/or speaking fees for non-CME services from Biogen, Mallinckrodt, Medtronic, Novartis, Sanofi, and Teva. DASC reports receiving consulting fees, grant, and research support from Sanofi, and lecture fees from Bayer-Schering Pharma and Sanofi, prior to 2017. ÓF reports receiving speaking and/or consulting fees for Allergan, Almirall, Bayer-Schering Pharma, Biogen, Merck Serono, Novartis, Sanofi, and Teva, and research support from the Hospital Foundation FIMABIS; he also serves as editor of the Revista Española de Esclerosis Múltiple. EKH reports receiving honoraria and grant support from Actelion, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, and Teva, and is supported by the Ministry of Education of the Czech Republic, project PROGRES Q27/LF1. KN reports speaking fees and research support from Biogen and Sanofi, along with royalty fees for licenses with Biogen. AT reports receiving consulting and/or speaking fees, along with grant and research support, from Biogen, Chugai, Roche, Sanofi, and Teva. TZ reports receiving consulting and/or speaking fees from Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva, along with grant and research support from Biogen, Novartis, Sanofi, and Teva. AJ, DHM, XH, and MCC report being employees of Sanofi during the time of the analysis. ND reports receiving personal compensation as an employee of Sanofi. KWS reports receiving consulting and/or speaking fees from Biogen, Merck, Novartis, Roche, Sanofi, and Synthon., (© The Author(s), 2021.)

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 to 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 exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 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 nine [17%], progressive symptoms in three [6%]: two [4%] patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 × 10-4, standard deviation [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 exposure were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not experience demyelination events. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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, p  = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number ( p  = 0.568) nor brain parenchymal fraction ( p  = 0.187) between those who relapsed within 4 years ( n  = 4) and those who did not ( n  = 15). However, the baseline gradient was significantly different ( p  = 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.

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 ( 1 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 13 C magnetic resonance imaging in the brain, in both clinical and pre-clinical studies.

Background: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years., Objective: To evaluate infections over 6 years in alemtuzumab-treated patients., Methods: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 μg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment., Results: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%-1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk., Conclusion: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

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.

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults in the developed world. The accuracy of early outcome-prediction remains poor even when all known prognostic factors are considered, suggesting important currently unidentified variables. In addition, whilst survival and neurological outcomes have improved markedly with the utilisation of therapies that optimise physiology, no treatments specifically modulate the underlying pathophysiology. The immunological response to TBI represents both a potential contributor to outcome heterogeneity and a therapeutically tractable component of the acute disease process. Furthermore, chronic inflammation has been linked with neurodegeneration, and may mark a bridge between acute brain injury and the subsequent neurodegenerative process seen in a proportion of patients following TBI. Given the complexity of the immune response and its varying functions ranging from repair of injury to bystander damage of healthy tissue, attempts at immunomodulatory intervention must necessarily be highly targeted towards the maladaptive facets of the inflammatory process. In this review we aim to provide an integrated description of the immunological processes triggered by TBI in both humans and animal models, in particular considering the interplay between the innate immune system, danger-associated molecular patterns and loss of self-tolerance leading to adaptive autoimmunity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.