Role of B Cells in Multiple Sclerosis and Related Disorders

Comı, Gıancarlo; Bar‐Or, Amit; Lassmann, Hans; Uccelli, Antonio; Hartung, Hans‐Peter; Montalbán, Xavier; Sørensen, P. S.; Hohlfeld, Reinhard; Hauser, Stephen L.

doi:10.1002/ana.25927

Cited by 167 publications

(117 citation statements)

References 102 publications

(102 reference statements)

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“…The significant effects of anti-CD20 mAbs on relapses may be partly explained by the ability of these medications to suspend a subset of B lymphocytes which are pathogenic in MS patients. Indeed, B cells are potent antigen presenting cells which mediate T cell activation, and they can also produce pathogenic antibodies ( Comi et al, 2020 ). Moreover, a subset of B cells are active producers of cytokines that regulate the proinflammatory (interleukin [IL]−6) as well as the anti-inflammatory responses (IL-10) ( Lehmann-Horn et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The comparative efficacy and safety of anti-CD20 monoclonal antibodies for relapsing-remitting multiple sclerosis: A network meta-analysis

Asha¹,

Al-Asaad²,

Khalil

2021

IBRO Neuroscience Reports

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With the recent successful targeting of B lymphocytes in patients with multiple sclerosis (MS), treatment with anti-CD20 monoclonal antibodies (mAbs) may represent a promising managemental approach, particularly for those with relapsing/remitting MS (RRMS). A network meta-analysis was conducted based on a comprehensive search in Embase, PubMed, and the Cochrane Library to assess the comparative efficacy and safety of currently available anti-CD20 monoclonal antibodies (mAbs), including rituximab, ocrelizumab, and ofatumumab, versus a common comparator (interferon beta-1a [INFβ-1a]) in RRMS patients recruited in randomized clinical trials (RCTs). In a frequentist network meta-analytical model, annualized relapse rates (ARRs) and safety outcomes were expressed as risk ratios (RRs), whereas relapse-free events were expressed as odds ratios (ORs). Treatment ranking was performed using P-scores. The certainty of evidence was appraised using the GRADE approach. Five publications reported the outcomes of seven RCTs (3938 patients, 67.09% females). Compared to INFβ-1a, ocrelizumab reduced the risk of ARR (RR = 0.56, 95% CI, 0.50–0.64), serious adverse events (RR = 0.17, 95% CI, 0.09–0.30), and treatment discontinuation due to adverse events (SAEs, RR = 0.60, 95% CI, 0.39–0.93), and it was associated with higher odds of no relapses (OR = 2.47, 95% CI, 2.00–3.05). Ocrelizumab ranked best among all other treatments in terms of reducing ARR and SAEs. The quality of evidence was low for ocrelizumab, low to moderate for rituximab, and high for ofatumumab. Further large-sized, well-designed RCTs are needed to corroborate the efficacy and safety of ocrelizumab and other anti-CD20 mAbs in RRMS.

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Section: Discussionmentioning

confidence: 99%

The comparative efficacy and safety of anti-CD20 monoclonal antibodies for relapsing-remitting multiple sclerosis: A network meta-analysis

Asha¹,

Al-Asaad²,

Khalil

2021

IBRO Neuroscience Reports

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“…The precise mechanisms underpinning the efficacy of CD20 cell depletion in MS and its animal models remain incompletely understood. 47 , 50 – 55 The interaction of specifically B and T cells may be particularly relevant to MS pathology. 56 The effectiveness of B-cell depletion in MS has been invoked to support the hypothesis that B cells latently infected with Epstein-Barr virus may play an important role in the pathogenesis of MS. 57 , 58 Animal studies have indicated that CD20 depletion modulates activation of monocytes and microglia and the recruitment of T lymphocytes.…”

Section: Msmentioning

confidence: 99%

Targeting B Cells to Modify MS, NMOSD, and MOGAD

Graf

Mareś

Barnett

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell–related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD), or are in advanced stages of clinical development. Currently, ocrelizumab, ofatumumab, and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This review focuses on the current state of knowledge about the role of B lymphocytes in immune-mediated pathophysiology and its implications for the mode of action. To understand the significance of this breakthrough in the context of the current MS therapeutic armamentarium, this review more closely examines the clinical development of CD20 depletion and the pioneering contribution of rituximab. Phase 3 and the recently published postmarketing studies will be highlighted to better understand the relevant efficacy data and safety aspects of long-term B-cell depletion.

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“… 35 However, it remains difficult to explain how B- cells’ accumulation as part of CNS-compartmentalized inflammation, may be limited by therapies as anti-CD20 antibodies that do not cross the blood–brain barrier (BBB). 36 …”

Section: B-cells In Ms: Implications For Clinical Use Of Anti-cd20 Mabsmentioning

confidence: 99%

Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology

Mancinelli¹,

Rossi²,

Capra³

2021

TCRM

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The success of selective B-cells depleting therapies, as the anti-CD20 antibodies, in patients with multiple sclerosis (MS) has confirmed that B-cells are critical in the immune pathogenesis of the disease. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20+ B-cells, profoundly suppresses acute inflammatory disease activity, representing a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS). It is also the first proven therapy able to slow disability progression in primary progressive multiple sclerosis (PPMS), particularly in patients with signs of acute radiological activity before being enrolled. Effectiveness has widely been demonstrated in randomized clinical trials (RCTs), and recently confirmed in open-label extension trials. Here, we review the role of B-cells in MS, the mechanism of action of ocrelizumab, its pharmacokinetics and pharmacodynamics, and the clinical data supporting its use, as well as safety data. We focus on issues related to the maintenance of immunocompetence, essential to ensure an immune response to either a primary infection or a vaccination. Lastly, we discuss about the possible role of ocrelizumab as an exit strategy from natalizumab-treated patients at risk of developing multifocal progressive leukoencephalopathy. In view of using ocrelizumab chronically, collecting long-term safety data and finding strategies to minimize adverse events will be extremely relevant.

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Role of B Cells in Multiple Sclerosis and Related Disorders

Cited by 167 publications

References 102 publications

The comparative efficacy and safety of anti-CD20 monoclonal antibodies for relapsing-remitting multiple sclerosis: A network meta-analysis

The comparative efficacy and safety of anti-CD20 monoclonal antibodies for relapsing-remitting multiple sclerosis: A network meta-analysis

Targeting B Cells to Modify MS, NMOSD, and MOGAD

Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology

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