215 results found
Nicholas RS, Rhone EE, Mariottini A, et al., 2021, Autologous Haematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: a Real-world Case Series., Neurology
OBJECTIVE: to examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting. METHODS: retrospective cohort study on PwMS treated with AHSCT at two centers in London, UK, consecutively between 2012 and 2019 who had ≥ 6 months of follow-up or died at any time. Primary outcomes were survival free of MS relapses, MRI new lesions and worsening of expanded disability status scale (EDSS). Adverse events rates were also examined. RESULTS: the cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS (RRMS). At baseline, the median expanded disability status scale (EDSS) was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of subjects at 2 years and 85% at 4 years. EDSS progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. EBV reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplant-related deaths within 100 days (2.5%), all following fluid overload and cardiac or respiratory failure. CONCLUSIONS: efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher. CLASSIFICATION OF EVIDENCE: this study is rated Class IV because of the uncontrolled, open-label design.
Amoriello R, Chernigovskaya M, Greiff V, et al., 2021, TCR repertoire diversity in Multiple Sclerosis: High-dimensional bioinformatics analysis of sequences from brain, cerebrospinal fluid and peripheral blood, EBioMedicine, Vol: 68, Pages: 103429-103429, ISSN: 2352-3964
BACKGROUND: T cells play a key role in the pathogenesis of multiple sclerosis (MS), a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Although several studies recently investigated the T-cell receptor (TCR) repertoire in cerebrospinal fluid (CSF) of MS patients by high-throughput sequencing (HTS), a deep analysis on repertoire similarities and differences among compartments is still missing. METHODS: We performed comprehensive bioinformatics on high-dimensional TCR Vβ sequencing data from published and unpublished MS and healthy donors (HD) studies. We evaluated repertoire polarization, clone distribution, shared CDR3 amino acid sequences (CDR3s-a.a.) across repertoires, clone overlap with public databases, and TCR similarity architecture. FINDINGS: CSF repertoires showed a significantly higher public clones percentage and sequence similarity compared to peripheral blood (PB). On the other hand, we failed to reject the null hypothesis that the repertoire polarization is the same between CSF and PB. One Primary-Progressive MS (PPMS) CSF repertoire differed from the others in terms of TCR similarity architecture. Cluster analysis splits MS from HD. INTERPRETATION: In MS patients, the presence of a physiological barrier, the blood-brain barrier, does not impact clone prevalence and distribution, but impacts public clones, indicating CSF as a more private site. We reported a high Vβ sequence similarity in the CSF-TCR architecture in one PPMS. If confirmed it may be an interesting insight into MS progressive inflammatory mechanisms. The clustering of MS repertoires from HD suggests that disease shapes the TCR Vβ clonal profile. FUNDING: This study was partly financially supported by the Italian Multiple Sclerosis Foundation (FISM), that contributed to Ballerini-DB data collection (grant #2015 R02).
Cencioni MT, Mattoscio M, Magliozzi R, et al., 2021, B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies, NATURE REVIEWS NEUROLOGY, Vol: 17, Pages: 399-414, ISSN: 1759-4758
Greco R, Alexander T, Burman J, et al., 2021, Hematopoietic stem cell transplantation for autoimmune diseases in the time of COVID-19: EBMT guidelines and recommendations, BONE MARROW TRANSPLANTATION, Vol: 56, Pages: 1493-1508, ISSN: 0268-3369
Burt RK, Muraro PA, Farge D, et al., 2021, New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis, BONE MARROW TRANSPLANTATION, Vol: 56, Pages: 1509-1517, ISSN: 0268-3369
Roberts F, Hobbs H, Jessop H, et al., 2020, Rehabilitation before and after Autologous Haematopoietic Stem Cell Transplantation (AHSCT) for patients with Multiple Sclerosis (MS): consensus guidelines and recommendations for best clinical practice on behalf of the autoimmune diseases working party, nurses group, and patient advocacy committee of the European Society for Blood and Marrow Transplantation (EBMT), Frontiers in Neurology, Vol: 11, Pages: 1-13, ISSN: 1664-2295
Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used to treat people with multiple sclerosis (MS). Supported by an evolving evidence base, AHSCT can suppress active inflammation in the central nervous system and induce long-term changes in immune cell populations, thereby stabilizing, and, in some cases, reversing disability in carefully selected MS patients. However, AHSCT is an intensive chemotherapy-based procedure associated with intrinsic risks, including profound cytopenia, infection, and organ toxicity, accompanied by an on-going degree of immuno-compromise and general deconditioning, which can be associated with a transient increase in functional impairment in the early stages after transplantation. Although international guidelines and recommendations have been published for clinical and technical aspects of AHSCT in MS, there has been no detailed appraisal of the rehabilitation needed following treatment nor any specific guidelines as to how this is best delivered by hospital and community-based therapists and wider multidisciplinary teams in order to maximize functional recovery and quality of life. These expert consensus guidelines aim to address this unmet need by summarizing the evidence-base for AHSCT in MS and providing recommendations for current rehabilitation practice along with identifying areas for future research and development.
Cencioni MT, Ali R, Nicholas R, et al., 2020, Defective CD19+CD24(hi)CD38(hi)transitional B-cell function in patients with relapsing-remitting MS, MULTIPLE SCLEROSIS JOURNAL, Vol: 27, Pages: 1187-1197, ISSN: 1352-4585
Iacobaeus E, Arrambide G, Amato MP, et al., 2020, Aggressive multiple sclerosis (1): Towards a definition of the phenotype., Multiple Sclerosis Journal, Vol: 26, Pages: 1031-1044, ISSN: 1352-4585
While the major phenotypes of multiple sclerosis (MS) and relapsing-remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.
The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients has what might be termed aggressive MS. These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability at the earlier stages of the disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive MS does not exist and data on its treatment are largely lacking. Based on discussions at an international focused workshop sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to fill those gaps. A companion paper details the difficulties in developing a consensus about what defines aggressive MS.
Mariottini A, De Matteis E, Muraro PA, 2020, Haematopoietic Stem Cell Transplantation for Multiple Sclerosis: Current Status, BIODRUGS, Vol: 34, Pages: 307-325, ISSN: 1173-8804
Lünemann JD, Ruck T, Muraro PA, et al., 2020, Author Correction: Immune reconstitution therapies: concepts for durable remission in multiple sclerosis., Nat Rev Neurol, Vol: 16
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Sharrack B, Saccardi R, Alexander T, et al., 2020, Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)., Bone Marrow Transplantation, Vol: 55, Pages: 283-306, ISSN: 0268-3369
These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
Harris KM, Lim N, Lindau P, et al., 2020, Extensive intrathecal T cell renewal following hematopoietic transplantation for multiple sclerosis, JCI INSIGHT, Vol: 5
Luenemann JD, Ruck T, Muraro PA, et al., 2020, Immune reconstitution therapies: concepts for durable remission in multiple sclerosis, NATURE REVIEWS NEUROLOGY, Vol: 16, Pages: 56-62, ISSN: 1759-4758
Mehra V, Rhone E, Widya S, et al., 2019, Epstein-barr virus and monoclonal gammopathy of clinical significance in autologous stem cell transplantation for multiple sclerosis., Clinical Infectious Diseases, Vol: 69, Pages: 1757-1763, ISSN: 1058-4838
INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. METHODS: Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. RESULTS: All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. CONCLUSION: Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT.
Muraro PA, Cohen JA, 2019, Complex intensive treatment shows promise against a complex aggressive disease, NEUROLOGY, Vol: 93, Pages: 776-777, ISSN: 0028-3878
Sridharan S, Raffel J, Nandoskar A, et al., 2019, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [18F]GE-180: a blocking study using XBD173 in multiple sclerosis normal appearing white and grey matter, Molecular Imaging and Biology, Vol: 21, Pages: 935-944, ISSN: 1536-1632
Purpose: Positron emission tomography (PET) ligands exhibit different levels of non-displaceable binding in vivo. In the case of ligands for the 18 kDa translocator protein (TSPO), the component of non-displaceable binding for the most widely used radiotracer, [11C]-(R)-PK11195, is relatively high compared to that for newer TSPO ligands. Non-displaceable binding is not often quantified in humans in vivo, partially due to a lack of available ligands that are known to be safe with which to displace binding to the target receptor. Recently, however, a technique has been developed to quantify the non-displaceable binding of TSPO tracers in vivo, by blocking the receptor with the TSPO ligand XBD173 and comparing the total volume of distribution ( ) pre and post-blockade. Here, we used an occupancy plot to quantify the non-displaceable binding ( ) of the TSPO PET tracers [18F]GE-180 and [11C]PBR28 in cohorts of people with multiple sclerosis (MS). We also compared plots of subjects carrying both high and mixed binding affinity polymorphisms of TSPO to estimate while potentially avoiding the need for receptor blockade.Procedures: Twelve people with multiple sclerosis (MS) and high (HAB) or mixed (MAB) affinity binding for TSPO underwent baseline MRI and 90-minute dynamic [18F]GE-180 PET (n=6; 3 HAB and 3 MAB) or [11C]PBR28 PET (n=6; 3 HAB, 3 MAB). Either one week later ([18F]GE-180) or the same afternoon ([11C]PBR28), participants had repeat PET following a 90mg dose of XBD173. PET images were co-registered with T1 MR volumetric images and regions of interest (ROIs) were defined using the 83-region Hammers atlas. Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model to quantify . The non-displaceable fraction of the total volume of distribution ( ) was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173), and the polymorphism plot (by modelling the differences in
Nicholas R, Chang K, Romozzi M, et al., 2019, Programmed cell death ligand 1 (PD-L1) in multiple sclerosis (MS) serum and cerebrospinal fluid (CSF), 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 444-445, ISSN: 1352-4585
Uccelli A, Laroni A, Brundin L, et al., 2019, MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a multi-center, randomized, double blind, cross-over phase 2 clinical trial with autologous mesenchymal stem cells (MSC), 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 759-760, ISSN: 1352-4585
Nicholas R, Cortese A, Hill J, et al., 2019, Early cervical spinal cord atrophy predicts disability in active relapsing multiple sclerosis: a longitudinal cohort study, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 472-472, ISSN: 1352-4585
Marastoni D, Magliozzi R, Howell O, et al., 2019, High levels of perivascular inflammation and active white matter lesions at time of death are associated with rapidly progressive multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 76-77, ISSN: 1352-4585
Rigoni E, Singh-Curry V, Nandoskar A, et al., 2019, Alemtuzumab as induction versus escalation therapy: efficacy and adverse events in the real-world, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 773-773, ISSN: 1352-4585
Ali R, Cencioni MT, Nicholas R, et al., 2019, Immunological change after MSC infusion in MS patients results from a Phase 2 trial of autologous mesenchymal cell therapy in MS (STREAMS), 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 297-298, ISSN: 1352-4585
Cencioni MT, Yusuf S, Palmisano I, et al., 2019, Soluble CD27 a biomarker of T cell activity in intrathecal inflammation in patients with relapsing-remitting multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 110-111, ISSN: 1352-4585
Scalfari A, Pisani A, Romualdi C, et al., 2019, Predictors of long term brain atrophy among multiple sclerosis patients, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 247-247, ISSN: 1351-5101
Uccelli A, Laroni A, Brundin L, et al., 2019, MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis, Trials, Vol: 20, Pages: 1-13, ISSN: 1745-6215
BackgroundMultiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS.Methods/designThis is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses.DiscussionResults will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials.
Cohen JA, Baldassari LE, Atkins HL, et al., 2019, Autologous hematopoietic cell transplantation for treatment-refractory relapsing multiple sclerosis: Position statement from the American Society for Blood and Marrow Transplantation, Biology of Blood and Marrow Transplantation, Vol: 25, Pages: 845-854, ISSN: 1083-8791
Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, central nervous system demyelinating and degenerative disease. Approved disease modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. Immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. Review of recent literature identified eight retrospective studies, eight clinical trials, and three meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapses, MRI lesion activity, and disability worsening, and to reverse disability, without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplant physicians with experience performing AHCT for autoimmune disease is crucial for appropriate patient selection and optimizing transplant procedures to improve patient outcomes. Transplant centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.
Muraro PA, Scolding NJ, Fox RJ, 2019, Author response: Rare side effects of alemtuzumab remind us of the need for postmarketing surveillance., Neurology, Vol: 92, Pages: 586-586
Sousa ADPA, Johnson KR, Ohayon J, et al., 2019, Comprehensive analysis of TCR-beta repertoire in patients with neurological immune-mediated disorders, Scientific Reports, Vol: 9, ISSN: 2045-2322
In this study we characterized the TCR repertoire profiles in patients with chronic progressive inflammatory neurological disorders including HAM/TSP, associated with human T-cell lymphotropic virus type I (HTLV-I) infection, and multiple sclerosis (MS), an inflammatory, demyelinating disease of the CNS of unknown etiology. We hypothesized that a T-cell receptor (TCR) clonal repertoire ‘signature’ could distinguish HAM/TSP patients from healthy controls, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease such as MS. In this study, we applied an unbiased molecular technique – unique molecular identifier (UMI) library-based strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). While HAM/TSP patients showed a higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subjects. In addition, longitudinal analysis of TCR repertoires from HAM/TSP patients demonstrated a correlation of the TCR clonal expansion with HTLV-I proviral load. Surprisingly, MS patients showed a higher diversity of TCR repertoires than other groups. Despite higher TCR clonal expansions in HAM/TSP patients, no disease-specific TCRs were shared among patients. Only non-shared or “private” TCR repertoires was observed. While no clones that shared the same CDR3 amino acid sequences were seen in either HC or MS patients, there was a cluster of related CDR3 amino acid sequences observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. This suggests that a TCR-repertoire signature may be identified in a subset of patients with MS.
Scalfari A, Nicholas R, Malik O, et al., 2018, Escalating Immunotherapies for highly active Multiple Sclerosis: reviewing the evidences, CML-Multiple Sclerosis
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