193 results found
Muraro PA, Cohen JA, 2019, Complex intensive treatment shows promise against a complex aggressive disease., Neurology, Vol: 93, Pages: 776-777
Lünemann JD, Ruck T, Muraro PA, et al., 2019, Immune reconstitution therapies: concepts for durable remission in multiple sclerosis., Nat Rev Neurol
New so-called immune reconstitution therapies (IRTs) have the potential to induce long-term or even permanent drug-free remission in people with multiple sclerosis (MS). These therapies deplete components of the immune system with the aim of allowing the immune system to renew itself. Haematopoietic stem cell transplantation, the oral formulation cladribine and the monoclonal antibodies alemtuzumab, rituximab and ocrelizumab are frequently categorized as IRTs. However, the evidence that IRTs indeed renew adaptive immune cell repertoires and rebuild a healthy immune system in people with MS is variable. Instead, IRTs might foster the expansion of those cells that survive immunosuppression, and this expansion could be associated with acquisition of new functional phenotypes. Understanding immunological changes induced by IRTs and how they correlate with clinical outcomes will be instrumental in guiding the optimal use of immune reconstitution as a durable therapeutic strategy. This Perspectives article critically discusses the efficacy and potential mechanisms of IRTs in the context of immune system renewal and durable disease remission in MS.
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
Sharrack B, Saccardi R, Alexander T, et al., 2019, 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, 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.
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
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.
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, Pages: 1-7, 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.
Scalfari A, Nicholas R, Malik O, et al., Escalating Immunotherapies for highly active Multiple Sclerosis: reviewing the evidences, CML-Multiple Sclerosis
Cencioni MT, Yang C-Y, Abrahamsson S, et al., 2018, Mechanisms of dysfunction of regulatory B cell activity in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 599-599, ISSN: 1352-4585
Muraro P, 2018, Immunological rationale., 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 68-68, ISSN: 1352-4585
Scalfari A, Lederer C, Daumer M, et al., 2018, Factors affecting mortality and causes of death among MS patients, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 137-137, ISSN: 1352-4585
Sridharan S, Raffel J, Nandoskar A, et al., 2018, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [F-18]GE-180: a blocking study using XDB173 in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 421-422, ISSN: 1352-4585
Rhone E, Nicholas R, Olavarria E, et al., 2018, Autologous stem cell transplantation in multiple sclerosis: the London experience, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 270-271, ISSN: 1352-4585
Scalfari A, Romualdi C, Magliozzi R, et al., 2018, Early cortical pathology and early relapses predict the risk of developing secondary progressive MS., 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 57-58, ISSN: 1352-4585
Muraro P, 2018, The rationale and the existing clinical data using haematopoietic stem cells in MS., 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 110-110, ISSN: 1352-4585
Scalfari A, Pisani AI, Romualdi C, et al., 2018, Early predictors of brain atrophy among MS patients, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 219-220, ISSN: 1352-4585
Alexander T, Farge D, Badoglio M, et al., 2018, Hematopoietic stem cell therapy for autoimmune diseases - Clinical experience and mechanisms, Journal of Autoimmunity, Vol: 92, Pages: 35-46, ISSN: 0896-8411
With accumulating evidence and improved outcomes along with recognition that modern biological therapies are not universally effective, require chronic administration and have high acquisition costs, hematopoietic stem cell transplantation (HSCT) has become an emerging direction for cell therapy in autoimmune diseases (ADs). The goal of this therapy is to induce medication-free remissions by resetting the immune system into a naïve and self-tolerant state through eradication of the autoreactive immunologic memory and profound re-configuration of the immune system induced by the transplant procedure. Safety of HSCT has generally improved by implementing internal quality management and external accreditation. Inter-disciplinary guidelines for patient selection, transplant technique and supportive care along with greater center experience should optimize safe and appropriate delivery of HSCT in specific ADs. In this review, we discuss the current role and future perspectives of HSCT in AD, focusing on recent published clinical and scientific studies and recommendations in the field.
Snowden JA, Sharrack B, Akil M, et al., 2018, Autologous haematopoietic stem cell transplantation (aHSCT) for severe resistant autoimmune and inflammatory diseases - a guide for the generalist, CLINICAL MEDICINE, Vol: 18, Pages: 329-334, ISSN: 1470-2118
Scalfari A, Romualdi C, Nicholas RS, et al., 2018, The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis, NEUROLOGY, Vol: 90, Pages: E2107-E2118, ISSN: 0028-3878
Objective To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS).Methods In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS.Results Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP.Conclusions Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy.
Muraro PA, Scolding NJ, Fox RJ, 2018, Rare side effects of alemtuzumab remind us of the need for postmarketing surveillance, NEUROLOGY, Vol: 90, Pages: 819-820, ISSN: 0028-3878
Sousa ADPA, Johnson K, Zhu J, et al., 2018, Deep sequencing of TCR beta-chain repertoire reveals an TCR expansion in patients with HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis and an immune profile signature in patients with Multiple Sclerosis, Publisher: SPRINGER, Pages: S22-S22, ISSN: 1557-1890
Sousa ADPA, Johnson K, Zhu J, et al., 2018, Deep sequencing of TCR ss-chain repertoire reveals an TCR expansion in patients with HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis and an immune profile signature in patients with Multiple Sclerosis, Joint Meeting of the International-Society-for-NeuroVirology (ISNV) and the Society-on-NeuroImmune-Pharmacology (SNIP), Publisher: SPRINGER, Pages: S22-S22, ISSN: 1355-0284
Mancardi G, Sormani MP, Muraro PA, et al., 2018, Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis, Multiple Sclerosis, Vol: 24, Pages: 245-255, ISSN: 1352-4585
In the majority of relapsing multiple sclerosis patients, the disease can be quite easily controlled by already available, approved therapies. There are, however, some aggressive cases who continue to have clinical and magnetic resonance imaging (MRI) activity in spite of the treatment. These are the cases who may now receive benefit from intense immunosuppression followed by autologous haematopoietic stem cell transplantation (aHSCT). In this review, we describe the method and the rationale of aHSCT, the more recently published studies that demonstrate its efficacy in selected multiple sclerosis cases, the problems related to safety and the transplant-related mortality risk of the procedure. A description of the ideal patient who can take advantage of aHSCT is outlined and, finally, the ongoing studies which are near to completion or are close to starting are briefly reported.
Magliozzi R, Roncaroli F, Muraro P, et al., 2017, The impact of high level of perivenular inflammation on active white matter lesions and disease progression in multiple sclerosis, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 172-172, ISSN: 1352-4585
Cencioni MT, Magliozzi R, Nicholas R, et al., 2017, Programmed death 1 is highly expressed on CD8(+) CD57(+) T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus., Immunology, Vol: 152, Pages: 660-676, ISSN: 0019-2805
Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8(+) T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8(+) CD57(+) T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8(+) CD57(+) T cells with high expression of PD-1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8(+) CD57(+) T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.
Rhone E, Silber E, Mccormick J, et al., 2017, Autologous haematopoietic stem cell transplant in multiple sclerosis: Updated results from the Pan-London MS group, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S482-S483, ISSN: 0268-3369
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