Clinical and immunological follow-up of B-cell depleting therapy in CNS demyelinating diseases

Gredler, Viktoria; Mader, Simone; Schanda, Kathrin; Hegen, Harald; Pauli, Franziska Di; Kuenz, Bettina; Deisenhammer, Florian; Berger, Thomas; Reindl, Markus; Lutterotti, Andreas

doi:10.1016/j.jns.2013.02.024

Cited by 24 publications

(20 citation statements)

References 30 publications

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“…In addition, a clonally expanded plasma cell population has been identified in the CSF of NMO patients, and the monoclonal recombinant antibodies generated from paired heavy and light chain sequences of these cells demonstrated AQP4 specificity (6). Rituximab, a chimeric monoclonal antibody recognizing CD20 that induces apoptosis and prolonged absence of circulating B cells (71), has been shown to be very effective in relapse prevention in NMO (14, 23, 24). This finding suggests B lymphocytes play a key role in the NMO relapse.…”

Section: Immunopathological Features Of Nmo Lesionsmentioning

confidence: 99%

The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica

et al. 2013

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Neuromyelitis optica (NMO) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally-extensive myelitis. Until recently, NMO was considered an acute aggressive variant of multiple sclerosis (MS), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody (NMO-IgG), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other CNS inflammatory demyelinating disorders. The target antigen of NMO-IgG was confirmed to be aquaporin-4 (AQP4), the most abundant water channel protein in the central nervous system (CNS), mainly expressed on astrocytic foot processes at the blood brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid (CSF) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF-GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro, ex vivo, and in vivo. These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO.

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Section: Immunopathological Features Of Nmo Lesionsmentioning

confidence: 99%

The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica

et al. 2013

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“…Open-label studies reported a significant reduction in relapse rate and subsequent stabilization or improvement in disability as measured by expanded disability status scale scores [63,[113][114][115][116][117]. Despite improving relapse rates and reducing disease activity reduced AQP4-IgG titers are not consistently associated with clinical improvement, even after long-term B-cell depletion [118]. In the largest cohort thus far, of 100 patients with NMO treated with rituximab, a 96% reduction of ARR compared with prerituximab treatment was noted [119].…”

Section: Inflammatory Myopathiesmentioning

confidence: 99%

“…It also remains uncertain why a number of relapses occur close to the initiation of rituximab treatment [62,118,121,122]. It has been observed that BAFF levels increase at the beginning of rituximab treatment and before the therapeutic depletion of CD27+ memory B cells takes place; this probably explains the increase in AQP4-IgG titers that is sometimes observed [62,118,121]. However, it is unclear whether these raises contribute to relapses because antibody titers do not correlate with disease activity [62,118,121].…”

Section: Inflammatory Myopathiesmentioning

confidence: 99%

“…It has been observed that BAFF levels increase at the beginning of rituximab treatment and before the therapeutic depletion of CD27+ memory B cells takes place; this probably explains the increase in AQP4-IgG titers that is sometimes observed [62,118,121]. However, it is unclear whether these raises contribute to relapses because antibody titers do not correlate with disease activity [62,118,121]. A recent case series of patients with NMO treated with rituximab reported that 6/17 patients experienced relapses within the first week of rituximab initiation [122].…”

Section: Inflammatory Myopathiesmentioning

confidence: 99%

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Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

2016

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B cells have an ever-increasing role in the etiopathology of a number of autoimmune neurological disorders, acting as antibody-producing cells and, most importantly, as sensors, coordinators, and regulators of the immune response. B cells, among other functions, regulate the T-cell activation process through their participation in antigen presentation and production of cytokines. The availability of monoclonal antibodies or fusion proteins against B-cell surface molecules or Bcell trophic factors bestows a rational approach for treating autoimmune neurological disorders, even when T cells are the main effector cells. This review summarizes basic aspects of B-cell biology, discusses the role(s) of B cells in neurological autoimmunity, and presents anti-B-cell drugs that are either currently on the market or are expected to be available in the near future for treating neurological autoimmune disorders.

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“…This fi nding was confi rmed by several groups using cellbased assays. Despite the reproducible detection of MOG-IgG antibodies in pediatric ADEM patients, all studies showed a variable degree of MOG-IgG detection in CNS demyelinating diseases and controls (Brilot et al 2009 ;Di Pauli et al 2011 ;Gredler et al 2013 ;Kitley et al 2012Kitley et al , 2014Lalive et al 2011 ;Mayer et al 2013 ;Mclaughlin et al 2009 ;Probstel et al 2011 ;Rostasy et al 2012Rostasy et al , 2013Sato et al 2014 ;Selter et al 2010 ;Titulaer et al 2014 ;Woodhall et al 2013 ). The clinical spectrum of MOG-IgG-associated CNS demyelinating diseases is broad, with a higher frequency of MOG-IgG found in pediatric patients with ADEM, CIS, MS, monophasic and recurrent optic neuritis and myelitis, NMO, and patients with NMDAR-encephalitis and demyelination.…”

Section: Antibodies To the Myelin Oligodendrocyte Glycoprotein (Mog) mentioning

confidence: 99%

Cerebrospinal Fluid in Clinical Neurology

Deisenhammer¹,

Sellebjerg²,

Teunissen³

et al. 2015

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Clinical and immunological follow-up of B-cell depleting therapy in CNS demyelinating diseases

Cited by 24 publications

References 30 publications

The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica

The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica

Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

Cerebrospinal Fluid in Clinical Neurology

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