Joost Smolders

Erasmus University Rotterdam, Neurology, Faculty Member

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Neurologist/ associate professor, working at MS center ErasMS, departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam (The Netherlands), and at the Neuroimmunology Researchgroup of Netherlands Institute for Neuroscience, Amsterdam (The Netherlands).
Address: Department of Neurology
Erasmus University Medical Center
Dr. Molewaterplein 40
3015 GD Rotterdam

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Jon R Sayers

The University of Sheffield

Annelise Barron

Stanford University

Carlo Semenza

Università degli Studi di Padova

Tulay Kansu

Hacettepe University

Stavros Baloyannis

Aristotelian University Thessaloniki

Kenneth Pakenham

The University of Queensland, Australia

Monica Ballarino

Università degli Studi "La Sapienza" di Roma

Rommy von Bernhardi

Pontificia Universidad Catolica de Chile

Marianna Mazza

Università Cattolica del Sacro Cuore (Catholic University of the Sacred Heart)

Susu Zughaier

Emory University

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Books by Joost Smolders

Chapter 9 - The way forward for vitamin D in multiple sclerosis.

Minagar A (ed.), Neuroinflammation (chapter 9, pp.1-17). Elsevier, Londen (UK). , 2018

Vitamin D exposure has gained interest as a potential disease modifying treatment in multiple scl... more Vitamin D exposure has gained interest as a potential disease modifying treatment in multiple sclerosis. First trials show a positive effect of vitamin D supplementation on several important MS related outcomes. Nevertheless, several issues need to be solved, centering around the questions why (which disease outcomes should be targeted), who (which patients at which stage in their disease or even healthy individuals prior to clinical disease onset) and how (which therapeutic strategies). In this chapter, we elaborate in detail on these issues. We conclude that there is consistent evidence for a beneficial effect of vitamin D supplements on selected disease outcomes in RRMS and CIS. The way forward for vitamin D in MS is the design of further supplementation trials to better understand and analyze the precise benefit of vitamin D supplements for our MS patients, and possibly also for subjects prior to clinical MS onset.

Chapter 25 - Shining light on Vitamin D and multiple sclerosis.

Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. More t... more Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. More than 2.3 million people are affected by MS worldwide. Symptoms can vary widely, depending on the localization and amount of the damage induced by combined inflammatory, demyelinating, and neurodegenerative processes. Although a cure for MS does not currently exist, therapies can help treat MS attacks, attenuate disease activity, reduce progress of the disease, and manage symptoms.
Translational Neuroimmunology in Multiple Sclerosis provides an overview of recent findings and knowledge of the neuroimmunology of multiple sclerosis, from experimental models and the human disease to the translation of this research to immunotherapeutic strategies. Chapters describe genetic and environmental factors underlying the disease pathogenesis of MS as a basis for development of immunotherapies, immunological markers of disease activity, pharmacogenetics, and responses to therapy. Immunomodulatory therapies currently in practice and future therapeutic strategies on the horizon—such as neuroprotective strategies, stem cells, and repair promotion—are discussed. Contributed by renowned leaders in the field, this cross-disciplinary volume is a great resource for basic scientists and clinical practitioners in neuroscience, neurology, immunology, pharmacology, and in-drug development.

Chapter 25 - Monitoring in vivo immune modulation by vitamin D in multiple sclerosis

Multiple sclerosis (MS) is a inflammatory, demyelinating disease of the central nervous system, c... more Multiple sclerosis (MS) is a inflammatory, demyelinating disease of the central nervous system, characterized by an auto-reactive T cell response. High serum 25-hydroxyvitamin D (25(OH)D) levels have been associated with decreased risk of developing MS and less severe disease. It is hypothesized that the underlying mechanism behind this association is the immune modulating effect of vitamin D on the adaptive immune response. In vitro studies and in vivo studies in the experimental autoimmune encephalomyelitis (EAE) animal model have shown consistently that immune cells are functional targets of vitamin D. However, in vivo studies in humans are limited. In this chapter, studies on the relation between vitamin D and immunological parameters in healthy individuals and patients with different auto immune disease, including MS, are evaluated. Correlation studies and supplementation studies performed thus far are heterogeneous in many aspects and studied a diverse repertoire of immunological outcome measures. Overall, there seems to be a trend towards an anti-inflammatory role of vitamin D, but this impression is not substantiated by conclusive data. Well-powered and controlled studies assessing disease-specific relevant immunological outcomes are warranted before conclusions can be drawn. Clinical trials on vitamin D supplementation in MS and other diseases may provide excellent frameworks for such studies.

Chapter 18 - Vitamin D as a T-cell Modulator in Multiple Sclerosis

Vitamin D is a potent immune modulator, keeping the T-cell compartment in a more tolerogenic stat... more Vitamin D is a potent immune modulator, keeping the T-cell compartment in a more tolerogenic state. Multiple sclerosis (MS), a disease in which an autoreactive T-cell response contributes to inflammation in the central nervous system, has been associated with vitamin D deficiency. The effects of vitamin D on the immune system are believed to be an important driver of this association. In this chapter, we elaborate on vitamin D as a modulator of the T-cell response. This discussion will be placed in the perspective of MS as a T-cell-mediated disease and in the perspective of the numerous association studies on vitamin D deficiency and multiple health outcomes. We conclude that there is a firm experimental and epidemiological basis supporting the model of vitamin D as a physiological immune modulator, on which intervention studies assessing clinical and immunological outcome measures should be designed.

Papers by Joost Smolders

Health-economic benefits of anti-CD20 treatments in relapsing multiple sclerosis estimated using a treatment-sequence model

Multiple sclerosis journal, experimental, translational and clinical, Jul 1, 2023

Background In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in t... more Background In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in the pipeline for relapsing MS: ocrelizumab, ofatumumab (both registered), ublituximab (awaiting registration) and rituximab (off-label). List prices differ significantly between registered and off-label drugs. Objective Comparing differences in benefits between anti-CD20 mAbs from a health-economic and societal perspective. Methods To reflect lifetime use of DMTs, we used a treatment-sequence model to compare ocrelizumab/ofatumumab and eight other drug classes in terms of health (lifetime relapses, time to Expanded Disability Status Scale [EDSS] 6, lifetime quality-adjusted life years) and cost-effectiveness (net health benefit). To become cost-effective compared to ocrelizumab, we modelled the list price of ublituximab and desired effect on EDSS progression of rituximab. Results Although drug sequences with ocrelizumab in first- and second-line were more cost-effective than ofatumumab, our probabilistic analysis suggests this outcome was very uncertain. To be more cost-effective than ocrelizumab, ublituximab needs to be about 25% cheaper whilst rituximab needs to equal the effect on disability progression seen with first-line treatments. Conclusions Our model showed no clear difference in cost-effectiveness between ocrelizumab and ofatumumab. Hence, prescribing the least costly anti-CD20 mAb can democratise MS care without a loss in health benefits.

Identification of neuropathology-based subgroups in multiple sclerosis using a data-driven approach

medRxiv (Cold Spring Harbor Laboratory), May 16, 2023

Multiple sclerosis (MS) is a heterogeneous disorder with regards to clinical presentation and pat... more Multiple sclerosis (MS) is a heterogeneous disorder with regards to clinical presentation and pathophysiology. Stratification into biologically distinct subgroups could enhance prognostication and efficacious allocation to disease-modifying therapies. In this study, we identified MS subgroups by performing a clustering analysis on neuropathology data collected for MS donors in the Netherlands Brain Bank (NBB) autopsy cohort. The input dataset contained detailed information on white matter lesion load, the proportion of active, mixed active/inactive, inactive and remyelinating lesions, microglia morphology in these lesions, and the presence of microglial nodules, perivascular cuffs and cortical lesions for 228 donors. A factor analysis was performed to reduce noise and redundancy prior to hierarchical clustering with K-means consolidation. Four subgroups with distinct patterns of white matter lesions were identified. These were subsequently validated with additional clinical, neuropathological and genetic data. The subgroups differed with regards to disease progression and duration, the timing of motor, sensory and other relevant signs and symptoms, patterns of cortical lesions and the presence of B cells. Age at MS onset and sex, previously associated with milder forms of MS, did not differ between the subgroups; the subgroups could also not be distinguished based on the manifestation of clinical signs and symptoms. The available genetic data was used to calculate MS polygenic risk scores (PRSs) for donors included in the NBB cohort. The MS PRS did not differ between the subgroups, but was significantly correlated with the first and second dimension of the factor analysis, the latter lending genetic support to our subdivision. Taken together, these findings suggest a complex relationship between neuropathological subgroups and clinical characteristics, indicating that post-mortem cohort studies are critical to better stratify patients and understand underlying neuropathophysiological mechanisms, in order to ultimately achieve personalised medicine in MS.

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Benefits of sphingosine-1-phosphate receptor modulators in relapsing MS estimated with a treatment sequence model

medRxiv (Cold Spring Harbor Laboratory), Dec 26, 2022

Background: Three sphingosine-1-phosphate receptor (S1PR) modulators are currently available as d... more Background: Three sphingosine-1-phosphate receptor (S1PR) modulators are currently available as disease-modifying therapies (DMTs) for relapsing MS in the Netherlands (i.e. fingolimod, ozanimod and ponesimod). We aimed to identify which S1PR modulator yields the highest benefit from a health-economic and societal perspective during a patient's lifespan. Methods: Incorporating Dutch DMT list prices, we used the ErasmusMC/iMTA MS model to compare DMT sequences, including S1PR modulators and eight other DMT classes, for treatment-naive patients with relapsing MS in terms of health outcomes (number of lifetime relapses, time to Expanded Disability Status Scale (EDSS) 6, lifetime quality-adjusted life years (QALYs)) and cost-effectiveness (net health benefit (NHB)). We estimated the influence of list price and EDSS progression on cost-effectiveness outcomes. Results: In deterministic and probabilistic analysis, DMT sequences with ponesimod have lower lifetime costs and higher QALYs resulting in a higher average NHB compared to sequences with other S1PR modulators. Ponesimod remains the most cost-effective S1PR modulator when EDSS progression is class-averaged. Given the variable effects on disability progression, list price reductions could make fingolimod but not ozanimod more cost-effective than ponesimod. Conclusion: Our model favours ponesimod among the S1PR modulators for the treatment of relapsing MS. This implies that prioritizing ponesimod over other S1PR modulators translates into a more efficacious spending of national healthcare budget without reducing benefit for people with MS. Prioritizing cost-effective choices when counselling patients contributes to affordable and accessible MS care.

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Ultrastructural Axon–Myelin Unit Alterations in <scp>Multiple Sclerosis</scp> Correlate with Inflammation

Annals of Neurology, Jan 5, 2023

ObjectiveChanges in the normal‐appearing white matter (NAWM) in multiple sclerosis (MS) may contr... more ObjectiveChanges in the normal‐appearing white matter (NAWM) in multiple sclerosis (MS) may contribute to disease progression. Here, we systematically quantified ultrastructural and subcellular characteristics of the axon–myelin unit in MS NAWM and determined how this correlates with low‐grade inflammation.MethodsHuman brain tissue obtained with short postmortem delay and fixation at autopsy enables systematic quantification of ultrastructural characteristics. In this study, we performed high‐resolution immunohis tochemistry and quantitative transmission electron microscopy to study inflammation and ultrastructural characteristics of the axon–myelin unit in MS NAWM (n = 8) and control white matter (WM) in the optic nerve.ResultsIn the MS NAWM, there were more activated and phagocytic microglia cells (HLA+P2RY12− and Iba1+CD68+) and more T cells (CD3+) compared to control WM, mainly located in the perivascular space. In MS NAWM compared to control WM, there were, as expected, longer paranodes and juxtaparanodes and larger overlap between paranodes and juxtaparanodes. There was less compact myelin wrapping, a lower g‐ratio, and a higher frequency of axonal mitochondria. Changes in myelin and axonal mitochondrial frequency correlated positively with the number of active and phagocytic microglia and lymphocytes in the optic nerve.InterpretationThese data suggest that in MS NAWM myelin detachment and uncompact myelin wrapping occurs, potassium channels are unmasked at the nodes of Ranvier, and axonal energy demand is increased, or mitochondrial transport is stagnated, accompanied by increased presence of activated and phagocytic microglia and T cells. These subclinical alterations to the axon–myelin unit in MS NAWM may contribute to disease progression. ANN NEUROL 2023;93:856–870

PND38 Optimal Treatment Sequence for Relapsing Remitting Multiple Sclerosis: Results from a Health Economic Modelling Study

Value in Health, 2020

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

Clusters of ramified HLA-DR+cells, known as microglia nodules, are associated with brain patholog... more Clusters of ramified HLA-DR+cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from microglia nodules in white matter (WM) in stroke and whether they may relate to the start of demyelinating MS lesions. We studied the relation between microglia nodules and pathological severity in an MS autopsy cohort (n=167), and we compared frequency, size, and gene expression of microglia nodules in MS (n=7) and stroke (n=7). MS donors with microglia nodules (64%) had a higher lesion load and a higher proportion of active lesions compared to donors without microglia nodules (36%). We found altered expression of genes in microglia nodules in MS compared to stroke, including genes previously shown to be upregulated in MS lesions. Genes associated with lipid metabolism, presence and proliferation of T and B cells, production of and response to immunoglobulins and cytokines (specifically TNF and IFN), activation of the complement cascade, and metabolic stress were upregulated. Using immunohistochemistry, we confirmed that in MS, more than in stroke, microglia nodules are associated with membrane attack complexes, have phagocytosed oxidized phospholipids, and have a tubular mitochondrial network reflecting increased metabolic activity. Furthermore, in MS, some nodules encapsulated partially demyelinated axons. Taken together, we propose that activation of some microglia nodules in MS by pro-inflammatory cytokines and immunoglobulins in combination with phagocytosis of oxidized phospholipids may lead to a volatile phenotype prone to form MS lesions.

Real-world challenges in the diagnosis of primary progressive multiple sclerosis

PubMed, Aug 14, 2023

Background and purpose: Despite the 2017 revisions to the McDonald criteria, diagnosing primary p... more Background and purpose: Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic challenges in a real-world setting and associate these with the performance of the 2010 and 2017 PPMS diagnostic McDonald criteria. Methods: Clinical, radiological and laboratory characteristics at the time of diagnosis were retrospectively recorded from designated PPMS patient files. Possible complicating factors were recorded such as confounding comorbidity, signs indicative of alternative diagnoses, possible earlier relapses and/or incomplete diagnostic work-up (no cerebrospinal fluid examination and/or magnetic resonance imaging brain and spinal cord). The percentages of patients fulfilling the 2010 and 2017 McDonald criteria were calculated after censoring patients with these complicating factors. Results: A total of 322 designated PPMS patients were included. Of all participants, it was found that n = 28/322 had confounding comorbidity and/or signs indicative of alternative diagnoses, n = 103/294 had possible initial relapsing and/or uncertainly progressive phenotypes and n = 73/191 received an incomplete diagnostic work-up. When applying the 2010 and 2017 diagnostic PPMS McDonald criteria on n = 118 cases with a full diagnostic work-up and a primary progressive disease course without a better alternative explanation, these were met by 104/118 (88.1%) and 98/118 remaining patients (83.1%), respectively (p = 0.15). Conclusion: Accurate interpretation of the initial clinical course, consideration of alternative diagnoses and a full diagnostic work-up are the cornerstones of a PPMS diagnosis. When these conditions are met, the 2010 and 2017 McDonald criteria for PPMS perform similarly, emphasizing the importance of their appropriate application in clinical practice.

Shedding Light on Vitamin D and Multiple Sclerosis

Abstract A poor circulating vitamin D status has been associated with an increased risk of develo... more Abstract A poor circulating vitamin D status has been associated with an increased risk of developing multiple sclerosis (MS) and with a more severe disease course of MS as reflected by clinical and radiological outcomes. As underlying mechanism, immune-modulating effects of vitamin D in the neurological periphery as well as within the borders of the central nervous system (CNS) have been proposed. The present chapter discusses studies in vitro, in experimental autoimmune encephalomyelitis, and in MS assessing the interaction of vitamin D metabolites with leukocytes and resident CNS cells. We conclude that an effect of vitamin D status, whether or not obtained by vitamin D supplementation in MS patients, on the behavior of these cells in secondary lymphoid organs and the CNS is plausible, but not yet proven. Upcoming clinical trials will provide biological material to assess this hypothesis.

Osteopontin associates with brain TRM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis

iScience, 2023

Highlights Human brain T cells possess a T RM-cell phenotypic and transcriptional profile Human b... more Highlights Human brain T cells possess a T RM-cell phenotypic and transcriptional profile Human brain T RM cells are characterized by CD20 and osteopontin expression In MS lesional T cells, the brain T RM-cell transcriptome is preserved MS lesional T RM cells produce less inflammatory cytokines on stimulation

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Effectiveness and Cost-Effectiveness of 360 Disease-Modifying Treatment Escalation Sequences in Multiple Sclerosis

Value in Health, Jun 1, 2022

Programmed Cell Death Protein 1–Positive CD8<sup>+</sup> T Cells in Multiple Sclerosis

Neuroimmunology and Neuroinflammation, Apr 22, 2022

Vitamin D as an immune modulator in multiple sclerosis, a review

Journal of Neuroimmunology, Feb 1, 2008

The role of vitamin D in calcium homeostasis is well known. More recently vitamin D has become a ... more The role of vitamin D in calcium homeostasis is well known. More recently vitamin D has become a topic of interest in immune regulation and multiple sclerosis. The main reason for this is the observed geographical distribution of multiple sclerosis. Areas with high sunlight exposure, the principal inducer of vitamin D synthesis, have a relatively low prevalence of multiple sclerosis and vice versa. Furthermore, low levels of the principal vitamin D metabolite (25-hydroxy vitamin D) in the circulation are associated with a high incidence of multiple sclerosis. Other epidemiological evidence also supports the view that vitamin D metabolites have an immune and disease modulating effect in multiple sclerosis. Experimental research in vitro and in animal models has further clarified the interaction of vitamin D metabolites with the immune system. The evidence obtained from these studies strongly supports a model in which vitamin D mediates a shift to a more anti-inflammatory immune response, and in particular to enhanced regulatory T cell functionality. In the current review we link the basic knowledge on vitamin D and immune regulation with the vitamin D related observations in multiple sclerosis. We conclude that there is a sound basis on which to initiate double-blind placebo-controlled trials that not only address the effect of vitamin D on the clinical outcome of multiple sclerosis, but also on the regulatory T cell compartment.

Considerations on vitamin D supplementation in multiple sclerosis

Elsevier eBooks, 2023

Epstein–Barr virus and genetic risk variants as determinants of T-bet+ B cell-driven autoimmune diseases

Immunology Letters

Improving Glucocorticoid Sensitivity of Brain-Homing CD4+ T Helper Cells by Steroid Hormone Crosstalk

Frontiers in Immunology

In early multiple sclerosis (MS), an IFN-γhighGM-CSFhighIL-17low CD4+ T-cell subset termed T help... more In early multiple sclerosis (MS), an IFN-γhighGM-CSFhighIL-17low CD4+ T-cell subset termed T helper 17.1 (Th17.1) reveals enhanced capacity to infiltrate the central nervous system. Th17.1 cells express high levels of multidrug resistance protein 1 (MDR1), which contributes to their poor glucocorticoid responsiveness. In this study, we explored whether glucocorticoid sensitivity of Th17.1 cells can generically be improved through synergy between steroid hormones, including calcitriol (1,25(OH)2D3), estradiol (E2) and progesterone (P4). We showed that human blood Th17.1 cells were less sensitive to 1,25(OH)2D3 than Th17 cells, as reflected by lower vitamin D receptor (VDR) levels and reduced modulation of MDR1, IFN-γ and GM-CSF expression after 1,25(OH)2D3 exposure. Upon T-cell activation, VDR levels were increased, but still lower in Th17.1 versus Th17 cells, which was accompanied by a 1,25(OH)2D3-mediated decline in MDR1 surface expression as well as secretion of IFN-γ and GM-CSF. ...

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Multiple sclerosis risk variants influence the peripheral B‐cell compartment early in life in the general population

European Journal of Neurology

Chapter 9 - The way forward for vitamin D in multiple sclerosis.

Minagar A (ed.), Neuroinflammation (chapter 9, pp.1-17). Elsevier, Londen (UK). , 2018

Chapter 25 - Shining light on Vitamin D and multiple sclerosis.

Chapter 25 - Monitoring in vivo immune modulation by vitamin D in multiple sclerosis

Chapter 18 - Vitamin D as a T-cell Modulator in Multiple Sclerosis

Health-economic benefits of anti-CD20 treatments in relapsing multiple sclerosis estimated using a treatment-sequence model

Multiple sclerosis journal, experimental, translational and clinical, Jul 1, 2023

Identification of neuropathology-based subgroups in multiple sclerosis using a data-driven approach

medRxiv (Cold Spring Harbor Laboratory), May 16, 2023

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Benefits of sphingosine-1-phosphate receptor modulators in relapsing MS estimated with a treatment sequence model

medRxiv (Cold Spring Harbor Laboratory), Dec 26, 2022

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Ultrastructural Axon–Myelin Unit Alterations in <scp>Multiple Sclerosis</scp> Correlate with Inflammation

Annals of Neurology, Jan 5, 2023

PND38 Optimal Treatment Sequence for Relapsing Remitting Multiple Sclerosis: Results from a Health Economic Modelling Study

Value in Health, 2020

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

Real-world challenges in the diagnosis of primary progressive multiple sclerosis

PubMed, Aug 14, 2023

Shedding Light on Vitamin D and Multiple Sclerosis

Osteopontin associates with brain TRM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis

iScience, 2023

Download

Effectiveness and Cost-Effectiveness of 360 Disease-Modifying Treatment Escalation Sequences in Multiple Sclerosis

Value in Health, Jun 1, 2022

Programmed Cell Death Protein 1–Positive CD8<sup>+</sup> T Cells in Multiple Sclerosis

Neuroimmunology and Neuroinflammation, Apr 22, 2022

Vitamin D as an immune modulator in multiple sclerosis, a review

Journal of Neuroimmunology, Feb 1, 2008

Considerations on vitamin D supplementation in multiple sclerosis

Elsevier eBooks, 2023

Epstein–Barr virus and genetic risk variants as determinants of T-bet+ B cell-driven autoimmune diseases

Immunology Letters

Improving Glucocorticoid Sensitivity of Brain-Homing CD4+ T Helper Cells by Steroid Hormone Crosstalk

Frontiers in Immunology

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Multiple sclerosis risk variants influence the peripheral B‐cell compartment early in life in the general population

European Journal of Neurology

Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

JCI Insight

fees from Biogen, Merck, Novartis, and Sanofi-Genzyme. RG was an employee of EMD Serono. UB is an... more

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Should anti-CD20 be used as an immune reconstitution therapy?

Multiple Sclerosis Journal

Brain-homing B cells in multiple sclerosis: association with Bruton’s tyrosine kinase and targeting by evobrutinib (4095)

Neurology, Apr 13, 2021

T cell composition and polygenic multiple sclerosis risk: A population‐based study in children

European Journal of Neurology, 2021

Patients with multiple sclerosis (MS) have altered T cell function and composition. Common geneti... more Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population.

Joost Smolders

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