scholarly journals Pharmacodynamic modeling and exposure-response assessment of inebilizumab in subjects with neuromyelitis optica spectrum disorders

2021 ◽  
Author(s):  
Li Yan ◽  
Bing Wang ◽  
Dewei She ◽  
Ben Mitchel ◽  
Ryan Criste ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neuromyelitis Optica ◽  
Drug Exposure ◽  
Response Assessment ◽  
Pharmacodynamic Modeling ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Spectrum Disorders ◽  
Disease Attack ◽  
The Impact

AIM: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell specific surface antigen CD19, resulting in rapid, profound, and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modeling of B cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome. METHODS: A hematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated. KEY RESULTS: At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium, and high PK exposure had a similar hazard ratio of NMOSD attack vs placebo group. CONCLUSIONS: The pharmacodynamic modeling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.

scholarly journals Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Malou Janssen ◽  
Arlette L Bruijstens ◽  
Jamie van Langelaar ◽  
YuYi Wong ◽  
Annet F Wierenga-Wolf ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neuromyelitis Optica ◽  
Immunoglobulin G ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Healthy Controls ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Toll Like Receptor ◽  
Spectrum Disorders

Abstract Neuromyelitis optica spectrum disorders are a group of rare, but severe autoimmune diseases characterized by inflammation of the optic nerve(s) and/or spinal cord. Although naive B cells are considered key players by escaping central tolerance checkpoints, it remains unclear how their composition and outgrowth differ in patients with neuromyelitis optica spectrum disorders. Under complete treatment-naive circumstances, we found that naive mature/transitional B-cell ratios were reduced in the blood of 10 patients with aquaporin-4 immunoglobulin G-positive disease (neuromyelitis optica spectrum disorders) as compared to 11 both age- and gender-matched healthy controls, eight patients with myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders and 10 patients with multiple sclerosis. This was the result of increased proportions of transitional B cells, which were the highest in patients with neuromyelitis optica spectrum disorders with relapses and strongly diminished in a separate group of nine patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders who received corticosteroid treatment. These findings need to be confirmed in longitudinal studies. For purified naive mature B cells of seven patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders with relapses, Toll-like receptor 9 ligand synergized with interferon-γ to enhance plasmablast formation during germinal centre-like cultures. This was not seen for 11 patients without relapses and nine healthy controls. In the neuromyelitis optica spectrum disorders group, in vitro plasmablast formation corresponded to total and anti-aquaporin-4 immunoglobulin G secretion, of which the latter was found only for relapsing cases. These data indicate that naive B-cell homoeostasis is different and selectively targeted by corticosteroids in patients with neuromyelitis optica spectrum disorders. This also supports further exploration of naive B cells for their use in Toll-like receptor 9-dependent in vitro platforms in order to predict the activity of neuromyelitis optica spectrum disorders.

The impact of 2015 neuromyelitis optica spectrum disorders criteria on diagnostic rates

2016 ◽  
Vol 23 (2) ◽  
pp. 228-233 ◽  
Author(s):  
Shahd HM Hamid ◽  
Liene Elsone ◽  
Kerry Mutch ◽  
Tom Solomon ◽  
Anu Jacob
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Neuromyelitis Optica ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
International Panel ◽  
Central Nervous System Demyelination ◽  
Spectrum Disorders ◽  
The Uk ◽  
The Impact ◽  
New Criteria

Background: The international panel for neuromyelitis optica (NMO) diagnosis has proposed diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD). Objectives: We assessed the impact of these criteria on diagnostic rates in a large cohort of patients. Methods: We identified and applied the 2006 and 2015 criteria to all patients ( n = 176) seen in the NMO and non-multiple sclerosis central nervous system demyelination clinic (part of the UK NMO service) from January 2013 to May 2015. Results: The 2006 criteria classified 63 of 176 (36%) patients as NMO. A total of 42 patients (67%) were aquaporin 4 (AQP4) immunoglobulin G (IgG) +ve and 21 (33%) AQP4 IgG −ve. The 2015 criteria classified 111 of 176 (63%) patients as NMOSD, of which 81 (73%) were AQP4 IgG +ve and 30 (27%) were AQP4 IgG −ve. There was an increase of 48 patients (76%) diagnosed as NMOSD using the new criteria. Conclusion: Application of the 2015 criteria led to a rise in diagnosis of NMOSD by 76%. The rise in the AQP4 IgG +ve group contributed 62% and the seronegative group contributed 14%.

Lymphocyte Subsets Are Associated with Disease Status in Neuromyelitis Optica Spectrum Disorders

2021 ◽  
pp. 1-10
Author(s):  
Hong Yang ◽  
Wei Liu ◽  
Yi-Fan Wu ◽  
De-Sheng Zhu ◽  
Xia-Feng Shen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
B Cells ◽  
Neuromyelitis Optica ◽  
Peripheral Blood ◽  
Lymphocyte Subsets ◽  
Disease Status ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Spinal Cord Lesions ◽  
Cross Sectional ◽  
Spectrum Disorders

<b><i>Objective:</i></b> At present, studies on lymphocytes are mostly conducted on CD19<sup>+</sup> B cells and CD27<sup>+</sup> B cells in neuromyelitis optica spectrum disorders (NMOSDs), but the exact changes in lymphocyte subsets (CD19<sup>+</sup> B cells, CD3<sup>+</sup> T cells, CD4<sup>+</sup> Th cells, CD8<sup>+</sup> Ts cells, the CD4<sup>+</sup>/CD8<sup>+</sup> ratio, and NK [CD56+ CD16] cells) have rarely been studied. This study aimed to assess lymphocyte subset changes in patients with NMOSD. <b><i>Methods:</i></b> We performed a cross-sectional study of consecutive patients with acute NMOSD (<i>n</i> = 41), chronic NMOSD (<i>n</i> = 21), and healthy individuals (<i>n</i> = 44). Peripheral blood samples were obtained upon admission, and lymphocyte subsets were analyzed by flow cytometry. Levels of lymphocyte subsets among 3 groups were compared and its correlation with the length of spinal cord lesions was analyzed. <b><i>Results:</i></b> The levels of peripheral blood CD19<sup>+</sup> B cells were significantly higher in patients with acute and chronic NMOSD than in healthy controls (HCs) (17.91 ± 8.7%, 13.08 ± 7.562%, and 12.48 ± 3.575%, respectively; <i>p</i> &#x3c; 0.001) and were positively correlated with the length of spinal cord lesions in acute NMOSD (<i>r</i> = 0.433, <i>p</i> &#x3c; 0.05). The peripheral blood CD4<sup>+</sup>/CD8<sup>+</sup> ratio was significantly lower in patients with acute NMOSD and chronic NMOSD than in HCs (1.497 ± 0.6387, 1.33 ± 0.5574, and 1.753 ± 0.659, respectively; <i>p</i> &#x3c; 0.05), and the levels of peripheral blood NK (CD56+ CD16) cells were significantly lower in patients with acute and chronic NMOSD than in HCs (13.6 ± 10.13, 11.11 ± 7.057, and 14.7 [interquartile range = 9.28], respectively; <i>p</i> &#x3c; 0.01). <b><i>Conclusions:</i></b> The levels of certain subsets of peripheral blood lymphocytes are associated with disease status in NMOSD.

scholarly journals Only Follow-Up of Memory B Cells Helps Monitor Rituximab Administration to Patients with Neuromyelitis Optica Spectrum Disorders

2018 ◽  
Vol 7 (2) ◽  
pp. 373-383 ◽  
Author(s):  
Christine Lebrun ◽  
Mikael Cohen ◽  
Maria Alessandra Rosenthal-Allieri ◽  
Saskia Bresch ◽  
Sylvia Benzaken ◽  
...  
Keyword(s):  
B Cells ◽  
Neuromyelitis Optica ◽  
Memory B Cells ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Spectrum Disorders

Circulating regulatory B cell subsets in patients with neuromyelitis optica spectrum disorders

2017 ◽  
Vol 38 (7) ◽  
pp. 1205-1212 ◽  
Author(s):  
Jinming Han ◽  
Li Sun ◽  
Zhongkun Wang ◽  
Xueli Fan ◽  
Lifang Wang ◽  
...  
Keyword(s):  
B Cell ◽  
Neuromyelitis Optica ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Regulatory B Cell ◽  
Spectrum Disorders ◽  
B Cell Subsets

scholarly journals COVID-19 in Patients With Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody Disease in North America

2021 ◽  
Vol 8 (5) ◽  
pp. e1057
Author(s):  
Scott D. Newsome ◽  
Anne H. Cross ◽  
Robert J. Fox ◽  
June Halper ◽  
Pamela Kanellis ◽  
...  
Keyword(s):  
Health Care Providers ◽  
Neuromyelitis Optica ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Small Sample ◽  
Clinical Severity ◽  
Categorical Variables ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Care Providers ◽  
Spectrum Disorders ◽  
The Impact

Background and ObjectiveTo describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).MethodsThe COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t-tests, Pearson χ2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity.ResultsAs of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%–75.5%]), whereas 15.6% (95% CI: 8.3%–25.6%) were hospitalized only, 9.1% (95% CI: 3.7%–17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%–19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79–19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated.DiscussionAmong the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size.

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