Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study

He, Anna; Merkel, B.; Brown, J William L; Ryerson, Lana Zhovits; Kister, Ilya; Malpas, Charles B; Sharmin, Sifat; Horáková, Dana; Havrdová, Eva; Spelman, Tim; Izquierdo, Guillermo; Eichau, Sara; Trojano, María; Lugaresi, Alessandra; Hupperts, Raymond; Sola, Patrizia; Ferraro, Diana; Lycke, Jan; Grand’Maison, François; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Larochelle, Catherine; Svenningsson, Anders; Petersen, Thor; Grammond, Pierre; Granella, Franco; Pesch, Vincent Van; Bergamaschi, Roberto; McGuigan, Christopher; Coles, Alasdair; Hillert, Jan; Piehl, Fredrik; Butzkueven, Helmut; Kalinčík, Tomáš

doi:10.1016/s1474-4422(20)30067-3

Cited by 235 publications

(223 citation statements)

References 25 publications

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“…Alemtuzumab induces long-term disease remission if treated sufficiently early after symptom onset (Cohen et al, 2012. Havrdova et al, 2017, He et al, 2020b. Two short cycles of treatment give long-term disease remission.…”

Section: Alemtuzumabmentioning

confidence: 99%

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

Baker

Amor

Kang

et al. 2020

Multiple Sclerosis and Related Disorders

103

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Background: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS. Objective: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis. Observations: Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm and vascular pathology appears to contribute to the damage in ARDS. Implications: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic. 1. SARS-Cov-2 and COVID-19 a new pandemic COVID-19 is the pandemic disease caused by severe acute respiratory syndrome (SARS) coronavirus two (SARS-CoV-2) infection (Zhu et al., 2020a; Zhou et al., 2020). About 80% of people infected with SARS-CoV-2 develop a self-limiting illness, 20% require hospitalisation, largely due to cardiovascular issues and about 5% require critical care and potential ventilatory support (Kimball et al., 2020; Day. 2020). The mortality in those requiring ventilatory support is about 40-50% (Weiss and Murdoch 2020; Zhu et al., 2020b). Death from COVID-19 is associated with older age and comorbidities such as cardiovascular disease, smoking, lung disease, obesity and diabetes (Zhu et al., 2020a; Lippi et al., 2020; Richardson et al., 2020). Mortality in young people and those without comorbidities may be related to excessive viral load (Lui et al 2020a; Chen et al., 2020a). Whilst the typical clinical features requiring self-isolation, and potentially hospitalization are fever, dry cough and shortness of breath related to respiratory tract infection, other symptoms such as headache and gastrointestinal symptoms may go unnoticed or under-appreciated leading to spreading of the virus (Zhu et al., 2020b; Richardson et al., 2020; Huang et al., 2020). People shed infective virus days before symptoms occur and continue to shed virus via the lungs and faeces whilst symptoms develo...

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Section: Alemtuzumabmentioning

confidence: 99%

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

Baker

Amor

Kang

et al. 2020

Multiple Sclerosis and Related Disorders

103

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“…Clinical support for this hypothesis has recently come from two retrospective studies suggesting that conversion to secondary progressive disease starts significantly earlier if the peripheral immune system is left unchecked. 34,35 However, long-term treatment with natalizumab and other high-efficacy immunomodulatory therapies is associated with serious side effects, such as potentially lethal JC virus reactivations and other severe infections 36,37 ; this has led to the current paradigm of treatment escalation commonly applied to RRMS patients, which is considered low risk in terms of side effects to the patients yet fails to eventually curb disease progression. Thus, a therapeutic strategy to prevent CNS-homing immune cells from establishing themselves in the brain early in disease would have to be highly targeted to be practicable.…”

Section: Ll Open Accessmentioning

confidence: 99%

Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

Kaufmann

Evans

Schaupp

et al. 2021

Med

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Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB). Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). Findings: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression.

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“…38 However, pronounced inflammatory activity and early brain volume loss is likely the harbinger of disability progression later, since the risk of clinical worsening is increasing with decreasing brain volume, 39 and treatment of early MS with efficacious medication is likely beneficial for long-term outcomes. 40 Some patients diagnosed with SPMS were young (e.g. ⩽25 or ⩽30 years of age) when enrolled.…”

Section: Characterisation Of Ms Phenotypes Across the Age Spanmentioning

confidence: 99%

Characterisation of MS phenotypes across the age span using a novel data set integrating 34 clinical trials (NO.MS cohort): Age is a key contributor to presentation

et al. 2021

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Background: The Oxford Big Data Institute, multiple sclerosis (MS) physicians and Novartis aim to address unresolved questions in MS with a novel comprehensive clinical trial data set. Objective: The objective of this study is to describe the Novartis–Oxford MS (NO.MS) data set and to explore the relationships between age, disease activity and disease worsening across MS phenotypes. Methods: We report key characteristics of NO.MS. We modelled MS lesion formation, relapse frequency, brain volume change and disability worsening cross-sectionally, as a function of patients’ baseline age, using phase III study data (≈8000 patients). Results: NO.MS contains data of ≈35,000 patients (>200,000 brain images from ≈10,000 patients), with >10 years follow-up. (1) Focal disease activity is highest in paediatric patients and decreases with age, (2) brain volume loss is similar across age and phenotypes and (3) the youngest patients have the lowest likelihood (<25%) of disability worsening over 2 years while risk is higher (25%–75%) in older, disabled or progressive MS patients. Young patients benefit most from treatment. Conclusion: NO.MS will illuminate questions related to MS characterisation, progression and prognosis. Age modulates relapse frequency and, thus, the phenotypic presentation of MS. Disease worsening across all phenotypes is mediated by age and appears to some extent be independent from new focal inflammatory activity.

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Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study

Cited by 235 publications

References 25 publications

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

Characterisation of MS phenotypes across the age span using a novel data set integrating 34 clinical trials (NO.MS cohort): Age is a key contributor to presentation

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