The success of clinical trials of selective B‐cell depletion in patients with relapsing multiple sclerosis (MS) and primary progressive MS has led to a conceptual shift in the understanding of MS ...pathogenesis, away from the classical model in which T cells were the sole central actors and toward a more complex paradigm with B cells having an essential role in both the inflammatory and neurodegenerative components of the disease process. The role of B cells in MS was selected as the topic of the 27th Annual Meeting of the European Charcot Foundation. Results of the meeting are presented in this concise review, which recaps current concepts underlying the biology and therapeutic rationale behind B‐cell–directed therapeutics in MS, and proposes strategies to optimize the use of existing anti–B‐cell treatments and provide future directions for research in this area. ANN NEUROL 2021;89:13–23
Fingolimod (FTY720) is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (MS). In vivo, fingolimod is ...phosphorylated to form fingolimod-phosphate, which resembles naturally occurring sphingosine 1-phosphate (S1P), an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors. There are at least 5 S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), 4 of which bind fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS. S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system (CNS). S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology, and migration. Fingolimod crosses the blood-brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies. Prophylactic administration of fingolimod to animals with experimental autoimmune encephalitis (EAE), a model of MS, completely prevents development of EAE features, whereas therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and 3 trials involving patients with relapsing or relapsing-remitting MS.
Infarcted regions of the brain after stroke are segregated from the intact brain by scar tissue comprising both fibrous and glial components. The extent and quality of scarring is influenced by ...inflammation. The matricellular glycoprotein osteopontin (OPN) is strongly induced in myeloid cells after stroke and may contribute to repair of ischemic brain lesions. To elucidate the role of OPN in scar formation, we induced photothrombotic brain infarction, characterized by circumscribed cortical infarctions with a well‐defined border zone toward the intact brain parenchyma. The cellular source and functional role of OPN was addressed by studies in OPN null (OPN‐/‐) mice, wild‐type mice depleted of hematogenous monocytes/macrophages by clodronate‐filled liposome treatment, and CCR2‐/‐ bone marrow chimeric mice characterized by impaired hematogenous macrophage influx into the infarctions. OPN was mainly produced by hematogenous macrophages infiltrating into the inner border zone of the infarcts whereas astrocyte activation occurred in the outer border zone. In OPN‐/‐ as well as macrophage‐depleted mice, reactive astrocytes failed to properly extend processes from the periphery toward the center of the infarctions. This was associated with incomplete coverage of neovessels by astrocytic endfeet and persistent leakiness of the damaged blood brain barrier. In conclusion, OPN produced by hematogenous macrophages induces astrocyte process extension toward the infarct border zone, which may contribute to repair of the ischemic neurovascular unit. GLIA 2015;63:2198–2207
Main Points
OPN produced by hematogenous MO/MP induces astrocyte polarization toward the border zone of brain infarcts.
This is important for neovessel coverage by astrocytic endfeet and re‐establishment of the blood brain barrier.
New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the ...highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.
Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance.The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV).Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS.
Patients with primary progressive MS who received the anti-CD20+ humanized antibody ocrelizumab were less likely to have clinical deterioration that was sustained for 12 weeks than those who received ...placebo. The drug was associated with decreased lesion activity on MRI.
Primary progressive multiple sclerosis accounts for 10 to 15% of the overall population with multiple sclerosis.
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The course of this disease differs from those of relapsing–remitting and secondary progressive forms of multiple sclerosis in that progression consists mainly of gradual worsening of neurologic disability from symptom onset, although relapses may occur.
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Phase 3 trials in primary progressive multiple sclerosis have been unsuccessful,
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and no disease-modifying treatments have been approved.
B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form.
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Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis . . .
Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than ...placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular interferon beta-1a in participants with relapsing multiple sclerosis.
SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18–55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0–5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, number NCT02294058 and EudraCT, number 2014–002320–27.
Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or interferon beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the interferon beta-1a group). Adjusted ARRs were 0·35 (0·28–0·44) for interferon beta-1a, 0·18 (95% CI 0·14–0·24) for ozanimod 1·0 mg (rate ratio RR of 0·52 0·41–0·66 vs interferon beta-1a; p<0·0001), and 0·24 (0·19–0·31) for ozanimod 0·5 mg (RR 0·69 0·55–0·86 vs interferon beta-1a; p=0·0013). Few ozanimod-treated participants discontinued treatment because of adverse events (13 2·9% who received ozanimod 1·0 mg; seven 1·5% who received ozanimod 0·5 mg; and 16 3·6% who received interferon beta-1a). No first-dose, clinically significant bradycardia or second-degree or third-degree atrioventricular block was reported. The incidence of serious adverse events was low and similar across treatment groups (13 2·9% participants who received ozanimod 1·0 mg; 16 3·5% who received ozanimod 0·5 mg; and 11 2·5% who received interferon beta-1a). No serious opportunistic infections occurred in ozanimod-treated participants.
In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than interferon beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis.
Celgene International II.
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