Rituximab in patients with pediatric multiple sclerosis and other demyelinating disorders of the CNS: Practical considerations

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

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Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US

Neurology ◽

10.1212/wnl.0000000000006471 ◽

2018 ◽

Vol 91 (19) ◽

pp. e1778-e1787 ◽

Cited By ~ 17

Author(s):

Kristen M. Krysko ◽

Jennifer Graves ◽

Mary Rensel ◽

Bianca Weinstock-Guttman ◽

Gregory Aaen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Side Effect ◽

Pediatric Patients ◽

Dimethyl Fumarate ◽

Short Term ◽

Pediatric Multiple Sclerosis ◽

Disease Modifying Therapies ◽

The Us ◽

Disease Modifying

ObjectiveTo characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age.MethodsThis is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005.ResultsAs of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ≥12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults.ConclusionNewer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management.

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International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions

Multiple Sclerosis Journal ◽

10.1177/1352458513484547 ◽

2013 ◽

Vol 19 (10) ◽

pp. 1261-1267 ◽

Cited By ~ 473

Author(s):

Lauren B Krupp ◽

Marc Tardieu ◽

Maria Pia Amato ◽

Brenda Banwell ◽

Tanuja Chitnis ◽

...

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Acute Disseminated Encephalomyelitis ◽

Study Group ◽

Pediatric Multiple Sclerosis ◽

Immune Mediated ◽

International Pediatric ◽

Demyelinating Disorders ◽

Multiple Sclerosis Study Group

Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. Objective: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. Methods: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. Results: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. Conclusions: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

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Nitrosative Stress Molecules in Multiple Sclerosis: A Meta-Analysis

Biomedicines ◽

10.3390/biomedicines9121899 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1899

Author(s):

Moritz Förster ◽

Christopher Nelke ◽

Saskia Räuber ◽

Hans Lassmann ◽

Tobias Ruck ◽

...

Keyword(s):

Multiple Sclerosis ◽

Nitrosative Stress ◽

Neurological Diseases ◽

Meta Analysis ◽

Statistical Significance ◽

Unknown Etiology ◽

Immune Mediated ◽

Pubmed Database ◽

The Central Nervous System ◽

Nitrite Nitrate

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system of unknown etiology. As it is still a diagnosis of exclusion, there is an urgent need for biomarkers supporting its diagnosis. Increasing evidence suggests that nitrosative stress may play a pivotal role in the pathogenesis of MS. However, previous reports supporting the role of nitrosative stress molecules as disease biomarkers are inconsistent overall. We therefore systematically analyzed the existing literature to compare the serum and cerebrospinal fluid (CSF) levels of nitrite/nitrate in MS patients with those in patients with noninflammatory other neurological diseases (NIOND) and healthy controls (HC), respectively. We searched the PubMed database and included original articles investigating nitrite/nitrate levels in MS patients and NIOND patients or HC based on predefined selection criteria. Effect sizes were estimated by the standardized mean difference using a random effects model. Our results suggest that MS is associated with higher nitrite/nitrate levels within the CSF compared with patients with NIOND (SMD of 1.51; 95% CI: 0.72, 2.30; p = 0.0008). Likewise, nitrite/nitrate in the CSF of MS patients trends towards increased levels compared with those of HC but does not reach statistical significance (SMD of 3.35; 95% CI: −0.48, 7.19; p = 0.07). Measurement of nitrite/nitrate in the CSF might be a valuable tool facilitating the differentiation of MS and NIOND. Further studies with more homogeneous study criteria are needed to corroborate this hypothesis.

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Pediatric Multiple Sclerosis: Current Concepts and Consensus Definitions

Autoimmune Diseases ◽

10.1155/2013/673947 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 10

Author(s):

Joaquin A. Pena ◽

Timothy E. Lotze

Keyword(s):

Multiple Sclerosis ◽

Clinical Symptoms ◽

Distinctive Features ◽

Pediatric Multiple Sclerosis ◽

Mcdonald Criteria ◽

Clinical Disorders ◽

Adults And Children ◽

The Central Nervous System ◽

Demyelinating Disorders ◽

Inflammatory Autoimmune Disease

Multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the central nervous system (CNS) commonly diagnosed in adults, is being recognized increasingly in children. An estimated 1.7%–5.6% of all patients with MS have clinical symptoms before reaching the age of 18 years. In comparison with adults, the diagnosis of MS in children can be more difficult, being dismissed or misdiagnosed as other clinical disorders. Although adults and children share basic aspects of the disorder, children have distinctive clinical features, neuroimaging, laboratory, and courses of the disease. The 2010 McDonald criteria have simplified the requirements for establishing the diagnosis of MS and have been proposed to be applicable for the diagnosis of pediatric MS, mainly in children 12 years and older. This paper describes the distinctive features of common pediatric demyelinating disorders, including MS, and summarizes the most recent advances based on the available literature.

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High Dose Cyclophosphamide for Moderate to Severe Refractory Multiple Sclerosis: 2-Year Follow-up (investigational new drug No. 65863).

Blood ◽

10.1182/blood.v114.22.4744.4744 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4744-4744

Author(s):

Douglas Gladstone

Keyword(s):

Multiple Sclerosis ◽

Brain Magnetic Resonance Imaging ◽

High Dose ◽

Immune Mediated ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Immune Manipulation ◽

Edss Score ◽

Disease Modifying Agents

Abstract Abstract 4744 Background High dose cyclophosphamide (HDC) is a chemotherapy treatment designed to eradicate autoreative B- and T-cells responsible for lymphocyte-mediated autoimmune illness, while sparing the pluripotent blood stem cell of any ill effects. Multiple sclerosis (MS) is the most common inflammatory and demyelinating immune-mediated disorder of the central nervous system in young adults. Methods Patients with moderate to severe, refractory MS, defined as an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after 2 or more Food and Drug Administration-approved disease-modifying agents, received 200 mg/kg of cyclophosphamide over 4 days. For the following 2 years, quarterly EDSS score evaluations and biannual brain magnetic resonance imaging and neuro-ophthalmologic evaluations were obtained. Results 15 patients were evaluated for clinical response. During follow-up, no patients increased their baseline EDSS score by more than 1.0. EDSS score stability or decrease was realized in 5 of 7 (71%) patients with relapsing remitting MS and 5 of 8 (62%) patients with secondary progressive MS patients. 4 patients required additional immunomodulatory treatment after treatment. Neurologic improvement involved changes in gait, bladder control, and visual function. Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. Conclusions HDC can effectively decrease symptoms, stop disease progression, and allow for disability regression in RR and SPMS patients. The most appropriate candidates for HDC, its duration of benefit and the potential need for prophylactic preventative immune manipulation after HDC all require further investigation. Disclosures: Off Label Use: cyclophosphamide: IND# 65863.

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GLATIRAMER ACETATE AND PREGNANCY IN WOMEN WITH MULTIPLE SCLEROSIS – RESULTS FROM THE GERMAN MULTIPLE SCLEROSIS AND PREGNANCY REGISTRY

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.40 ◽

2015 ◽

Vol 101 (1) ◽

pp. e1.35-e1 ◽

Cited By ~ 1

Author(s):

Sandra Herbstritt ◽

Ralf Gold ◽

Kerstin Hellwig

Keyword(s):

Multiple Sclerosis ◽

Glatiramer Acetate ◽

Perinatal Outcome ◽

Neurological Diseases ◽

Reproductive Age ◽

Limited Data ◽

The Central Nervous System ◽

Exposure During Pregnancy ◽

Pregnancy Registry

ObjectiveTo determine the effect of glatiramer acetate (GLAT) exposure during pregnancy on perinatal outcome in women with multiple sclerosis (MS).BackgroundMS is one of the most common neurological diseases of the central nervous system, which mainly affects young women of reproductive age.Only limited data are available on whether GLAT exposure during pregnancy has an effect on perinatal outcome.MethodsWe compared the outcome of pregnancies of patients with MS exposed to GLAT with pregnancies of unexposed controls. Women with MS were enrolled into the German Multiple Sklerosis and pregnancy registry. Data were assessed with a standardized questionnaire during pregnancy and the postpartum year. Detailed information on course of MS, concomitant medication, pregnancy course and outcome was obtained.ResultsWe collected data on 230 pregnancies: 135 with exposure to GLAT and 95 MS controls unexposed to disease-modifying therapies (DMTs) during pregnancy.While 25 of the exposed pregnancies are still ongoing we did not document any malformation in the first 110 GLAT exposed pregnancies with at least 6 months postpartum follow up. The rate of spontaneous abortions did not differ compared to unexposed controls. 3 (3.15%) infants of the DMT unexposed women were born with malformations of non-genetic origin and 1 (0.95%) newborn was diagnosed with Wolf Hirschhorn syndrome.ConclusionsGLAT exposure does not constitute a major human teratogen or influence outcome of pregnancy negatively compared to untreated women with MS. Final data including the outcome of ongoing pregnancies will be presented at the time of the meeting.

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GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

Science Translational Medicine ◽

10.1126/scitranslmed.aat4301 ◽

2018 ◽

Vol 10 (462) ◽

pp. eaat4301 ◽

Cited By ~ 19

Author(s):

Raquel Planas ◽

Radleigh Santos ◽

Paula Tomas-Ojer ◽

Carolina Cruciani ◽

Andreas Lutterotti ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

Cell Clone ◽

Autoimmune Response ◽

Guanosine Diphosphate ◽

Immune Mediated ◽

T Cell Clone ◽

Positional Scanning ◽

The Central Nervous System

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

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Demyelinating disorders of the central nervous system

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.0241002_update_001 ◽

2010 ◽

pp. 4948-4963

Author(s):

Siddharthan Chandran ◽

Alastair Compston

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Acute Disseminated Encephalomyelitis ◽

Demyelinating Diseases ◽

Demyelinating Disorder ◽

System P ◽

The Central Nervous System ◽

Demyelinating Disorders ◽

Brain And Spinal Cord

Clinicians suspect demyelination when episodes reflecting damage to white matter tracts within the central nervous system occur in young adults. The paucity of specific biological markers of discrete demyelinating syndromes places an emphasis on clinical phenotype—temporal and spatial patterns—when classifying demyelinating disorders. The diagnosis of multiple sclerosis, the most common demyelinating disorder, becomes probable when these symptoms and signs recur, involving different parts of the brain and spinal cord. Other important demyelinating diseases include post-infectious neurological disorders (acute disseminated encephalomyelitis), demyelination resulting from metabolic derangements (central pontine myelinosis), and inherited leucodystrophies that may present in children or in adults. Accepting differences in mechanism, presentation, and treatment, two observations can usefully be made when classifying demyelinating disorders. These are the presence or absence of inflammation, and the extent of focal vs. diffuse demyelination. Multiple sclerosis is prototypic for the former, whereas dysmyelinating disorders, such as leucodystrophies are representative of the latter....

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Immune and Infectious Diseases

Mayo Clinic Essential Neurology ◽

10.1093/med/9780190206895.003.0013 ◽

2018 ◽

pp. 430-470

Author(s):

Andrea C. Adams

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Young People ◽

Connective Tissue ◽

Infectious Diseases ◽

Temporal Profile ◽

Immune Mediated ◽

The Central Nervous System ◽

The Common

Many immune-mediated diseases and infections affect the central and peripheral nervous systems. The common feature that characterizes both immune-mediated diseases and infections is a subacute temporal profile. Immune-mediated disease can affect only the nervous system or involve the nervous system as part of a systemic illness, as in vasculitis and connective tissue disease. Multiple sclerosis (MS), the most common disabling neurologic illness of young people, is the prototypical immune-mediated disease of the central nervous system (CNS).

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