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

Background: Atypical myelitis in multiple sclerosis (MS) is characterized by extensive myelitis in the longitudinal (longitudinally extensive transverse myelitis) or axial plane (transverse myelitis). Objective: To characterize a cohort of MS patients with atypical myelitis. Methods: Atypical myelitis was extracted from the French and Luxembourg MS databases and compared to two cohorts of MS patients with typical myelitis and neuromyelitis optica spectrum disorders (NMOSDs) patients with myelitis. Results: We enrolled 28 MS patients with atypical myelitis, 68 MS patients with typical myelitis and 119 NMOSD patients with a first episode of myelitis. MS patients with atypical myelitis were characterized by a mean age of 34.0 (±10.7) years and 64.3% were women. In 82.1% of the patients, atypical myelitis was the first episode of MS. Mean Expanded Disability Status Scale (EDSS) scores at nadir and 3–6 months after onset were 4.1 ± 2.1 and 3.3 ± 2, respectively. Differences between groups revealed a predominance of cervicothoracic myelitis and a higher level of disability in NMOSD patients. Disability in MS patients with atypical myelitis was more severe than in the MS patients with typical myelitis; 28% had already converted to progressive MS within our mean follow-up of 39.6 (±30.4) months. Conclusion: Atypical myelitis may be the first presentation of MS and is associated with poorer prognosis.

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

10.22541/au.163676321.19163981/v1 ◽

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.

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Five-year follow-up of pediatric onset Neuromyelitis Optica Spectrum Disorders (NMOSD)

10.26226/morressier.59a3e8b4d462b8028d8941eb ◽

2017 ◽

Author(s):

Renata Paolilo

Keyword(s):

Neuromyelitis Optica ◽

Neuromyelitis Optica Spectrum Disorders ◽

Spectrum Disorders ◽

Pediatric Onset

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

NeuroImmunoModulation ◽

10.1159/000520745 ◽

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

Objective: At present, studies on lymphocytes are mostly conducted on CD19+ B cells and CD27+ B cells in neuromyelitis optica spectrum disorders (NMOSDs), but the exact changes in lymphocyte subsets (CD19+ B cells, CD3+ T cells, CD4+ Th cells, CD8+ Ts cells, the CD4+/CD8+ ratio, and NK [CD56+ CD16] cells) have rarely been studied. This study aimed to assess lymphocyte subset changes in patients with NMOSD. Methods: We performed a cross-sectional study of consecutive patients with acute NMOSD (n = 41), chronic NMOSD (n = 21), and healthy individuals (n = 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. Results: The levels of peripheral blood CD19+ 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; p < 0.001) and were positively correlated with the length of spinal cord lesions in acute NMOSD (r = 0.433, p < 0.05). The peripheral blood CD4+/CD8+ 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; p < 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; p < 0.01). Conclusions: The levels of certain subsets of peripheral blood lymphocytes are associated with disease status in NMOSD.

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A long-term follow-up of rituximab treatment in 20 Chinese patients with neuromyelitis optica spectrum disorders

Multiple Sclerosis and Related Disorders ◽

10.1016/j.msard.2020.101933 ◽

2020 ◽

Vol 40 ◽

pp. 101933

Author(s):

Qianshuo Lu ◽

Jingjing Luo ◽

Hongjun Hao ◽

Ran Liu ◽

Haiqiang Jin ◽

...

Keyword(s):

Neuromyelitis Optica ◽

Chinese Patients ◽

Neuromyelitis Optica Spectrum Disorders ◽

Long Term Follow Up ◽

Spectrum Disorders

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Treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders with rituximab using a maintenance treatment regimen and close CD19 B cell monitoring. A six-year follow-up

Journal of the Neurological Sciences ◽

10.1016/j.jns.2016.11.016 ◽

2017 ◽

Vol 372 ◽

pp. 92-96 ◽

Cited By ~ 10

Author(s):

M.E. Evangelopoulos ◽

E. Andreadou ◽

G. Koutsis ◽

V. Koutoulidis ◽

M. Anagnostouli ◽

...

Keyword(s):

B Cell ◽

Treatment Regimen ◽

Neuromyelitis Optica ◽

Maintenance Treatment ◽

Neuromyelitis Optica Spectrum Disorders ◽

Cell Monitoring ◽

Spectrum Disorders

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Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG–Associated Disease and Neuromyelitis Optica Spectrum Disorders

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001100 ◽

2021 ◽

Vol 9 (1) ◽

pp. e1100

Author(s):

Marius Ringelstein ◽

Ilya Ayzenberg ◽

Gero Lindenblatt ◽

Katinka Fischer ◽

Anna Gahlen ◽

...

Keyword(s):

Neuromyelitis Optica ◽

Interleukin 6 ◽

Neuromyelitis Optica Spectrum Disorders ◽

Class Iii ◽

Disability Status ◽

Interleukin 6 Receptor ◽

Spectrum Disorders ◽

The Brain

Background and ObjectivesTo evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).MethodsAnnualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.ResultsPatients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

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

Brain Communications ◽

10.1093/braincomms/fcaa197 ◽

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.

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