Author Of 1 Presentation
PS15.03 - Optical coherence tomography in aquaporin-4-IgG positive neuromyelitis optica spectrum disorders: a collaborative multi-center study
- F. Oertel
- S. Specovius
- H. Zimmermann
- C. Chien
- S. Motamedi
- L. Cook
- M. Lana-Peixoto
- M. Fontenelle
- H. Kim
- J. Hyun
- J. Palace
- A. Roca-Fernandez
- F. Ashtari
- R. Kafieh
- L. Pandit
- A. D'Cunha
- O. Aktas
- M. Ringelstein
- E. May
- C. Tongco
- L. Leocani
- M. Pisa
- M. Radaelli
- E. Martinez-Lapiscina
- H. Stiebel-Kalish
- S. Siritho
- J. De Seze
- T. Senger
- J. Havla
- R. Marignier
- E. Nerrant
- A. Cobo Calvo
- D. Bichuetti
- I. Tavares
- N. Asgari
- K. Soelberg
- A. Altintas
- U. Tanriverdi
- A. Jacob
- S. Huda
- Z. Rimler
- Y. Mao-Draayer
- I. Soto De Castillo
- A. Green
- M. Yeaman
- T. Smith
- A. Brandt
- F. Paul
Abstract
Background
Optic neuritis (ON) is a frequent manifestation in aquaporin-4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (NMOSD). Due to limited samples, existing optical coherence tomography (OCT) studies are inconsistent regarding retinal changes in eyes with a history of ON (NMO-ON) and without a history of ON (NMO-NON), and their functional relevance.
Objectives
The CROCTINO (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica) project aims to reveal correlates of retinal pathology and to generate hypotheses for prospective OCT studies in NMOSD. The objective of this study was to analyze retinal changes of AQP4-IgG seropositive NMO-ON and NMO-NON eyes in an international cross-sectional OCT dataset.
Methods
Of 656 subjects, we enrolled 283 AQP4-IgG seropositive NMOSD patients and 72 healthy controls (HC) from 22 international expert centers. OCT data was acquired with Spectralis SD-OCT, Cirrus HD-OCT and Topcon 3D OCT-1. Mean thickness for the combined ganglion cell and inner plexiform layer (GCIP) and inner nuclear layer (INL) were calculated from macular volume scans. Clinical, functional and laboratory testing were performed at discretion of each center.
Results
We compared NMO-ON eyes (N = 260), NMO-NON eyes (N = 241) and HC eyes (N = 136). GCIP was reduced in NMO-ON (57.4 ± 12.2 µm) compared with NMO-NON (75.9 ± 7.7 µm; p < 0.001) and HC (81.4 ± 5.7 µm; p < 0.001). NMO-NON had thinner GCIP (p < 0.001) compared with HC. INL was thicker in NMO-ON (40.3 ± 3.9 µm) compared with NMO-NON (38.6 ± 3.9µm; p < 0.001), but not HC (39.4 ± 2.6 µm). Microcystic macular edema were visible in 6.6 % of NMOSD eyes.
Conclusions
AQP4-IgG seropositive NMOSD is characterized by a functionally relevant loss of retinal neuroaxonal content and a - probably inflammatory - increase of INL after ON. Our study further supports the existence of attack-independent damage in the visual system of patients with AQP4-IgG seropositive NMOSD.
Author Of 4 Presentations
LB1177 - PAMRINO: International MRI and clinical data repository for neuromyelitis optica spectrum disorder (ID 469)
- C. Chien
- H. Zimmermann
- S. Specovius
- F. Oertel
- D. Bichuetti
- M. Idagawa
- A. Altintas
- U. Tanriverdi
- S. Siritho
- L. Pandit
- A. D'Cunha
- M. Sá
- R. Figueiredo
- C. Tongco
- P. Qian
- I. Lotan
- V. Khasminsky
- M. Hellmann
- H. Stiebel-Kalish
- D. Rotstein
- L. Waxman
- D. Ontaneda
- K. Nakamura
- H. Abboud
- M. Subei
- Y. Mao-Draayer
- J. Havla
- N. Asgari
- I. Kister
- Z. Rimler
- A. Reid
- M. Ringelstein
- S. Broadley
- S. Arnett
- B. Marron
- A. Jolley
- M. Wunderlich
- S. Green
- L. Cook
- M. Yeaman
- T. Smith
- A. Brandt
- P. Skejø
- V. Cruz Silva
- J. Wuerfel
- F. Paul
- G. International Clinical Consortium For Nmosd
Abstract
Background
Neuromyelitis optica spectrum disorders (NMOSD) encompasses a group of rare inflammatory diseases which primarily target the optic nerves, spinal cord, and brain. Typically, magnetic resonance imaging (MRI) data from single-center studies comprise 20-50 patients, limiting statistical power for outcomes research. Using retrospective data from the PArallel MRI in NmOsd (PAMRINO) study, a novel prospective NMOSD image repository (NMOsDIR) representing multiple international sites was coordinated by Charité-Universitätsmedizin Berlin and the Medical Image Analysis Center (Basel).
Objectives
The PAMRINO study aimed to investigate and analyze retrospective MRIs collected from NMOSD-specialized centers, potentially for the evaluation of disease-related brain and spinal cord changes. NMOsDIR serves as an international imaging research resource (comprising standardized retinal optical coherence tomography and MRI scans) and clinical data hub for prospective studies in NMOSD. Linking imaging and clinical data, as well as enabling analysis pipelines for each modality, will facilitate multi-centered studies using sufficient data and statistical power to advance outcomes research in this rare disease.
Methods
For clinical data collection in PAMRINO, a Research Electronic Data Capture (REDCap) platform was used, where participating centers entered data relevant for NMOSD patient monitoring. An image database (XNAT) was established for image uploads. This large collection of MRI data is currently being analyzed in a joint international effort of NMOSD clinical neuroradiologists and scientists.
Results
Brain, spinal cord, and optic nerve MRI scans with associated clinical data were collected from 514 NMOSD patients and 56 healthy controls from 17 international centers. Roughly 20,000 individual MRI scans from patients and healthy controls were collected. Of these, 78% had T1-weighted cerebral MRIs (55% with 3D scans), 80% had T2-weighted cerebral MRIs (54% with 3D scans), 86% had T2-weighted spinal cord MRIs (55% with 3D scans), and 35% had optic nerve MRIs.
Conclusions
We successfully established PAMRINO, an international collaborative retrospective MRI and clinical data repository. The knowledge gained during this process provided important new insights, where the initial analysis of the dataset has underscored the large degree of heterogeneity in image and clinical data collection in NMOSD-specialized centers. Thus, calling for more standardized methods of data acquisition and imaging analysis, as not to limit research opportunities. The new longitudinal, prospective NMOsDIR will help us to answer many pressing - yet open - questions regarding patients seropositive for aquaporin-4-IgG+, myelin oligodendrocyte glycoprotein-IgG+ and other autoimmune-related diseases. In turn, such a strategy will strengthen future capabilities in research, diagnosis, monitoring and improving NMOSD patient care.
LB1267 - Teriflunomide Enhanced Innate and Adaptive Immune Regulatory Function in Treating Multiple Sclerosis (ID 2165)
Abstract
Background
The efficacy and safety of Teriflunomide (AubagioTM), a disease-modifying therapy (DMT) for relapsing multiple sclerosis (RMS) have been well established in pivotal trials. However, its mechanism of action on adaptive and innate immune cell compartments is yet to be elucidated.
Objectives
To report detailed immune phenotyping and immune cell function analysis from a prospective phase 4 study of relapsing MS patients receiving teriflunomide (NCT03464448).
Methods
27 subjects (age 18-65) were recruited from the University of Michigan MS Center who had been previously diagnosed with relapsing MS and were undergoing therapy with teriflunomide. Blood samples were collected for immunophenotyping and functional analysis. Peripheral blood mononuclear cells (PBMCs) were separated and stained with antibodies to examine cell subsets and analyzed by multicolor flow cytometry. Both adaptive and innate immune cell lineages at baseline pre-treatment and periodically for up to 2 years post teriflunomide treatment were studied.
Results
Teriflunomide treatment showed minimal effect on the frequencies and absolute counts of CD4+ T cells; it moderately reduced the frequency of CD8+ T cells, NK, and NKT cells. It significantly reduced the frequency NK cells, particularly pathogenic CD56dim NK cells, therefore reduced CD56dim/CD56hi ratio. Functional analysis revealed that NK cells from teriflunomide treated patients had increased trend of degranulation. In addition, teriflunomide also increased the expression CD39 and percentage of CD39+ Tregs, which implies an enhanced Treg suppressive function. Furthermore, teriflunomide decreased CXCR3 expression on T helper (Th) cells, which suggests impediment of pathogenic Th cells. Finally, teriflunomide showed a diminishing trend of the frequency of total B cells (specifically switched memory B cells) while it increased naïve B cells and downregulated the expression of co-stimulatory molecules CD80 and CD86.
Conclusions
In conclusion, teriflunomide promotes a tolerogenic immune response and suppresses the pathogenic immune response in relapsing MS patients.
P0213 - Immune cell profiles and clinical and safety outcomes with fingolimod in the 12 month FLUENT study of patients with relapsing multiple sclerosis (ID 1750)
Abstract
Background
FLUENT investigated immune cell subset changes in the innate and adaptive immune systems during fingolimod therapy, and their associations with efficacy and safety outcomes.
Objectives
To report changes in immune cell profile, efficacy and safety of fingolimod 0.5 mg/day in adults with relapsing multiple sclerosis (RMS).
Methods
In FLUENT (NCT03257358), a prospective, 12 month, phase 4, multicenter, nonrandomized, open-label study, patients were stratified as fingolimod naive (Cohort 1) or previously treated with fingolimod 0.5 mg/day continuously for ≥2 years (Cohort 2). Primary outcome was change from Baseline to Month 12 in immune cell subsets. Secondary outcomes included Patient Determined Disease Steps (PDDS), anti-John Cunningham virus (anti-JCV) antibody status, serum neurofilament light chain (NfL) concentration, and adverse events (AEs) incidence. Data were analyzed from all patients completing Month 12 follow-up.
Results
165 patients enrolled in Cohort 1; 217 in Cohort 2. Proportionally more patients in Cohort 1 than Cohort 2 relapsed in the year before baseline. At Baseline, patients in Cohort 1 had proportionally more naive and central memory CD4+ and CD8+ T cells and memory B cells, and proportionally fewer effector memory CD4+ and CD8+ T cells and regulatory B cells, than those in Cohort 2. At Month 12, between-cohort differences in the proportions of these lymphocyte types/subtypes were much reduced or negligible. Levels were essentially unchanged in Cohort 2, indicating reductions in naive T cells and increases in effector memory T cells and regulatory B cells in Cohort 1. Mean baseline PDDS scores were low (Cohort 1, 1.7; Cohort 2, 1.8), and changed little by Month 12. Median change from Baseline in anti-JCV antibody index was small in both cohorts. Proportions of patients with positive JCV serology remained stable at Month 12 (61% and 67% in Cohorts 1 and 2 vs 57% and 65% at Baseline). Mean serum NfL level was higher in Cohort 1 than Cohort 2 at Baseline (12.2 vs 9.6 pg/mL); levels were similar at Month 12 (8.7 vs 9.8 pg/mL), having reduced substantially in Cohort 1. Proportionally more patients in Cohort 1 than in Cohort 2 had treatment-emergent AEs (54.6% vs 44.2%), and discontinued study treatment (12.3% vs 5.5%); 5.5% of patients in each cohort reported serious AEs.
Conclusions
These data expand our knowledge of changes in immune cell profiles over time in patients with RMS treated with fingolimod in the short or long term.
P0233 - Safety and tolerability of conversion to siponimod in patients with relapsing multiple sclerosis: interim results of the EXCHANGE study (ID 1134)
Abstract
Background
In the USA, siponimod is approved in adults for the treatment of relapsing multiple sclerosis (RMS), including active secondary progressive MS (SPMS). Understanding washout requirements when converting from other disease-modifying treatments (DMTs) to siponimod is important in clinical practice and should be assessed prospectively.
Objectives
To report results from an interim analysis of EXCHANGE (NCT03623243), a prospective, 6 month, multicenter, open-label, single-arm study evaluating safety and tolerability of overlapping effects when converting to siponimod from other DMTs.
Methods
Patients aged 18-65 years with advancing RMS, Expanded Disability Status Scale (EDSS) score of >2.0 to 6.5, and on continuous oral/injectable DMTs for ≥3 months at time of consent were included in the analysis. Patients were immediately converted to siponimod, except those previously on teriflunomide who required 11-14 days’ washout (with cholestyramine or activated charcoal). During days 1-6, siponimod was titrated from 0.25 mg to 2 mg. Primary endpoint was incidence of drug-related adverse events (AEs). About 100 patients are being enrolled in a parallel, novel virtual cohort, with telemedicine tools.
Results
112 patients (1 in the virtual arm; 70.5% female) from 42 centers in the USA were enrolled, completed screening and were eligible for safety analysis (33.9% ongoing; 20.5% discontinued; 45.5% completed). At screening, 74.1% (n=83) of patients had relapsing-remitting MS, 21.4% (n=24) had SPMS, 3.6% (n=4) had primary progressive MS and 0.9% (n=1) had a single demyelinating event; 42.0% (n=47) had ≥1 relapse in the prior 12 months. At baseline, median age was 45.5 years, median time since MS diagnosis was 11.2 years and median EDSS score was 3.5. In the safety analysis set, ≥1 drug-related AE was reported in 34.8% of patients (n=39) (95% confidence interval [CI]: 26.2-44.5); 4.5% (n=5) had ≥1 serious AE and 5.4% (n=6) had ≥1 AE leading to drug discontinuation. In the subgroup of patients who had completed or discontinued from the study (n=74), 40.5% (n=30) (95% CI: 29.5-52.6) had ≥1 drug-related AE. Change from baseline in heart rate to 6 hours post first dose and AEs by prior DMT will be presented.
Conclusions
Conversion from oral/injectable DMTs to siponimod without washout had a good safety and tolerability profile with no unexpected findings. Subsequent analyses will include data on conversion to siponimod from infusible (natalizumab/ocrelizumab) DMTs.
Presenter Of 2 Presentations
LB1267 - Teriflunomide Enhanced Innate and Adaptive Immune Regulatory Function in Treating Multiple Sclerosis (ID 2165)
Abstract
Background
The efficacy and safety of Teriflunomide (AubagioTM), a disease-modifying therapy (DMT) for relapsing multiple sclerosis (RMS) have been well established in pivotal trials. However, its mechanism of action on adaptive and innate immune cell compartments is yet to be elucidated.
Objectives
To report detailed immune phenotyping and immune cell function analysis from a prospective phase 4 study of relapsing MS patients receiving teriflunomide (NCT03464448).
Methods
27 subjects (age 18-65) were recruited from the University of Michigan MS Center who had been previously diagnosed with relapsing MS and were undergoing therapy with teriflunomide. Blood samples were collected for immunophenotyping and functional analysis. Peripheral blood mononuclear cells (PBMCs) were separated and stained with antibodies to examine cell subsets and analyzed by multicolor flow cytometry. Both adaptive and innate immune cell lineages at baseline pre-treatment and periodically for up to 2 years post teriflunomide treatment were studied.
Results
Teriflunomide treatment showed minimal effect on the frequencies and absolute counts of CD4+ T cells; it moderately reduced the frequency of CD8+ T cells, NK, and NKT cells. It significantly reduced the frequency NK cells, particularly pathogenic CD56dim NK cells, therefore reduced CD56dim/CD56hi ratio. Functional analysis revealed that NK cells from teriflunomide treated patients had increased trend of degranulation. In addition, teriflunomide also increased the expression CD39 and percentage of CD39+ Tregs, which implies an enhanced Treg suppressive function. Furthermore, teriflunomide decreased CXCR3 expression on T helper (Th) cells, which suggests impediment of pathogenic Th cells. Finally, teriflunomide showed a diminishing trend of the frequency of total B cells (specifically switched memory B cells) while it increased naïve B cells and downregulated the expression of co-stimulatory molecules CD80 and CD86.
Conclusions
In conclusion, teriflunomide promotes a tolerogenic immune response and suppresses the pathogenic immune response in relapsing MS patients.
P0213 - Immune cell profiles and clinical and safety outcomes with fingolimod in the 12 month FLUENT study of patients with relapsing multiple sclerosis (ID 1750)
Abstract
Background
FLUENT investigated immune cell subset changes in the innate and adaptive immune systems during fingolimod therapy, and their associations with efficacy and safety outcomes.
Objectives
To report changes in immune cell profile, efficacy and safety of fingolimod 0.5 mg/day in adults with relapsing multiple sclerosis (RMS).
Methods
In FLUENT (NCT03257358), a prospective, 12 month, phase 4, multicenter, nonrandomized, open-label study, patients were stratified as fingolimod naive (Cohort 1) or previously treated with fingolimod 0.5 mg/day continuously for ≥2 years (Cohort 2). Primary outcome was change from Baseline to Month 12 in immune cell subsets. Secondary outcomes included Patient Determined Disease Steps (PDDS), anti-John Cunningham virus (anti-JCV) antibody status, serum neurofilament light chain (NfL) concentration, and adverse events (AEs) incidence. Data were analyzed from all patients completing Month 12 follow-up.
Results
165 patients enrolled in Cohort 1; 217 in Cohort 2. Proportionally more patients in Cohort 1 than Cohort 2 relapsed in the year before baseline. At Baseline, patients in Cohort 1 had proportionally more naive and central memory CD4+ and CD8+ T cells and memory B cells, and proportionally fewer effector memory CD4+ and CD8+ T cells and regulatory B cells, than those in Cohort 2. At Month 12, between-cohort differences in the proportions of these lymphocyte types/subtypes were much reduced or negligible. Levels were essentially unchanged in Cohort 2, indicating reductions in naive T cells and increases in effector memory T cells and regulatory B cells in Cohort 1. Mean baseline PDDS scores were low (Cohort 1, 1.7; Cohort 2, 1.8), and changed little by Month 12. Median change from Baseline in anti-JCV antibody index was small in both cohorts. Proportions of patients with positive JCV serology remained stable at Month 12 (61% and 67% in Cohorts 1 and 2 vs 57% and 65% at Baseline). Mean serum NfL level was higher in Cohort 1 than Cohort 2 at Baseline (12.2 vs 9.6 pg/mL); levels were similar at Month 12 (8.7 vs 9.8 pg/mL), having reduced substantially in Cohort 1. Proportionally more patients in Cohort 1 than in Cohort 2 had treatment-emergent AEs (54.6% vs 44.2%), and discontinued study treatment (12.3% vs 5.5%); 5.5% of patients in each cohort reported serious AEs.
Conclusions
These data expand our knowledge of changes in immune cell profiles over time in patients with RMS treated with fingolimod in the short or long term.