Faculty Bibliography

Introduction: Optical coherence tomography (OCT) is a valuable tool for quantifying retinal neuro-axonal damage in Neuromyelitis Optica Spectrum Disorders (NMOSD). However, existing OCT studies in NMOSD reveal inconsistencies due to non-standardised methods and limited sample sizes.
Objective(s): To collect and uniformly analyze a large international OCT dataset with corresponding clinical data for correlates of retinal damage in NMOSD in a multicenter approach (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica, CROCTINO).
Aim(s): To facilitate optimization of international OCT standards, reveal potential correlates of NMOSD disease and retinal pathology, and generate hypotheses for prospective studies.
Method(s): Centers were mainly recruited from the GJCF-ICC network including experts in NMOSD clinical care and research. OCT images were collected as source data to allow for standardised quality control and analysis. Demographic and clinical metadata were obtained with electronic record forms, adhering to institutional review board approval. We included subjects with a) NMOSD per the 2015 International Panel criteria; b) longitudinal extensive transverse myelitis; c) recurrent optic neuritis; and d) healthy controls. Only subjects with available OCT source data and a complete information on age, sex, disease subtype and attack history were included.
Result(s): Data from 501 cases from 20 international centers were collected (148 Asia, 249 Europe, 36 North America, 68 South America). Age was 44+/-15 years (range, 10-85 years), with 84% female. A total of 470 patients fulfilled the 2015 NMOSD criteria, with 345 (73.4%) seropositive for aquaporin4 antibodies (AQP4- IgG) using a validated method. Of the AQP4-IgG-negative patients, 47 (37.6%; 9.4% of all patients) were MOG antibody seropositive, and 78 (62.4%, 15.6% of all patients) were double negative or had unknown antibody status. OCT was performed in 344 patients using Spectralis SD-OCT, in 102 using Cirrus HD-OCT and 55 using Topcon 3D OCT instruments. Healthy control data were available from 90 subjects from 4 centers (all Spectralis)
Conclusion(s): CROCTINO has collected the largest OCT dataset from NMOSD patients to date. Results from this international collaborative study should facilitate improved OCT practices in NMOSD, highlight clinical correlates of disease and retinal status, and prioritize hypothesis-testing to advance clinical care and research goals in the future

Introduction: The availability of numerous highly efficacious therapies for multiple sclerosis (MS) has ignited debate about whether early aggressive treatment is more favourable than the traditional approach of escalation after failure of first line therapies.
Aim(s): To compare patients' long-term disability outcomes following high efficacy therapy commenced either early or late in their disease course.
Method(s): Data were extracted from MSBase, an international observational MS registry, as well as two local databases (Cambridge and Dublin). We identified patients with relapsing remitting MS who commenced high-efficacy disease modifying therapies (Rituximab, Ocrelizumab, Mitoxantrone, Alemtuzumab, Natalizumab) either 0-2 years (early) or >4 years (late) after clinical disease onset. Indication bias was minimised by propensity score matching on demographic and clinical variables in the first two years of disease. Outcomes were assessed at years 6 to 10 after disease onset. The primary outcome was difference in disability in each year of disease, as measured by the Expanded Disability Status Score (EDSS). Secondary outcomes were cumulative hazard of confirmed disability progression and hazard of treatment discontinuation.
Result(s): There were 170 patients who commenced high-efficacy therapy at 0-2 years (early) and 578 patients who commenced at >4 years (late). During years 0-2, the early group had a higher cumulative hazard of confirmed disability progression; the inverse was true after year 2. For the year 6 outcomes analysis, 117 patients in the early group were propensity score matched to 181 patients in the late group. At baseline, the mean(SD) EDSS was 2.3(1.3) vs 2.3(1.2) in the early vs late groups. At six years, the mean(SD) EDSS was 2.5(1.8) in the early group, compared to 3.4(1.7) in the late group (p< .001). This difference remained clinically (>=.5 EDSS steps) and statistically (p<= .05) significant up to 10 years post disease onset.
Conclusion(s): Patients with MS commencing high-efficacy immunotherapy early after disease onset accumulate less long-term disability compared to those exposed later in their disease. Those treated earlier had a more aggressive disease course initially, which was then mitigated by their early active management strategy. In patients with highly active MS, early high efficacy therapy is recommended

Background: SymptoMScreen is a new patient-reported outcome (PRO) tool for the rapid assessment of multiple sclerosis (MS) symptom severity in 12 domains (walking, hand function/dexterity, spasticity, bodily pain, sensory, bladder, fatigue, vision, dizziness, cognitive, depression and anxiety) on 7-point Likert scales (0 [not affected] to 6 [total limitation]). SymptoMScreen is used for the first time as an outcome measure in two ongoing, openlabel, single-arm Phase IIIb clinical trials of ocrelizumab (OCR) in treatment naive patients with early-stage relapsing-remitting MS (RRMS; ENSEMBLE [NCT03085810]) and patients with RRMS who had a prior suboptimal response to disease-modifying treatment (DMT; CASTING [NCT02861014]).
Objective(s): To report ENSEMBLE and CASTING baseline SymptoMScreen results.
Method(s): Patients in ENSEMBLE (Expanded Disability Status Scale [EDSS] score <=3.5 at screening) had a disease duration of <=3 years and >=1 clinically reported relapse or >=1 sign of MRI activity within 12 months of enrolment; patients in CASTING (EDSS <=4.0 at screening) had a disease duration <=10 years and discontinued a prior DMT of >=6 months' duration for reasons of suboptimal disease control. SymptoMScreen was performed in all study patients at baseline. OCR 600mg/24 weeks (first dose, 2x300mg, 14 days apart) was administered intravenously in both ENSEMBLE (192 weeks; maximum 8 doses) and CASTING (96 weeks; maximum 4 doses).
Result(s): ENSEMBLE patient (N=676) baseline characteristics were: female=65%, mean (SD) baseline EDSS score=1.7 (1.0), disease duration=1.1 (0.9) years; and in CASTING (N=681): female=64%, baseline EDSS score=2.1 (1.1), disease duration= 5.0 (2.7) years. In CASTING, 61% of patients had received one DMT prior to enrolment (most frequently dimethyl fumarate [25%]). Total mean (SD) baseline SymptoMScreen scores were 12.2 (10.9) in ENSEMBLE and 15.3 (12.6) in CASTING; individual domain scores ranged from 0.8 (1.1) to 1.8 (1.5) and 1.0 (1.2) to 2.1 (1.6), respectively, with numerically higher scores in ENSEMBLE (all domains) and fatigue having the highest score in both studies. Moderate to severe fatigue (domain score >=3) was reported in 31% (ENSEMBLE) to 41% (CASTING) of patients.
Conclusion(s): SymptoMScreen scores were generally low, though expectedly higher in CASTING than ENSEMBLE, consistent with greater disability in the patients who experienced suboptimal control; differences were consistent in all domains, but were most pronounced in fatigue and ambulation

Background: Natural history studies in MS largely focused on determining time-to-disability benchmarks. Little is known about changes in MS symptom burden from patient's point of view. SymptoMScreen is an in-house developed and validated patientreported outcome (PRO) tool for assessing symptom severity in 12 domains commonly affected by

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system autoimmune inflammatory condition associated with aquaporin-4-immunglobulin antibodies which results in demyelination. Understanding clinical and therapeutic predictors of relapses can aid management and prognostication of this disease Aim: To evaluate the effect of clinical and therapeutic predictors on risk of relapse and change in disability in NMOSD Methods: This MSBase cohort study of NMOSD patients (n=399) examined predictors of relapse in a Anderson-Gill survival model and change in expanded disability status score (EDSS) in a mixed effects model. A secondary analysis was conducted in the NMOantibody positive subgroup (>=1 core region affected: spinal cord, optic nerve or brainstem, n=202).
Result(s): Age (HR=0.82 per decade, p=0.003), disease duration (HR=0.95 per year, p=0.02), spinal cord onset (HR=0.6, p=0.007), brainstem onset (p=0.53, p=0.009) and treatment with azathioprine (HR=0.51, p< 0.001), mycophenolate mofetil (HR=0.24, p=0.016) were associated with a reduced risk of relapse in NMOSD. Treatment with glatiramer acetate (HR=1.82, p=0.028), interferon-beta (HR=1.57, p=0.013) and acute therapies-corticosteroids (HR=1.87, p < 0.001), intravenous immunoglobulin (HR=3.49, p=0.001) were associated with an increased risk of relapse. In the NMO-antibody positive subgroup, similar treatment effects on the risk of relapse were seen for azathioprine, mycophenolate mofetil, glatiramer acetate, corticosteroids and intravenous immunoglobulin. Age (p< 0.001), disease duration (p< 0.001), glatiramer acetate (p=0.001), and therapies used in acute relapses-cyclophosphamide (p=0.01), intravenous immunoglobulin (p=0.001) and plasma exchange (p< 0.001) were associated with a more pronounced increase in EDSS in the NMOSD cohort. Optic nerve onset (p=0.048), proportion of time pregnant (p=0.021) and treatment with azathioprine (p< 0.001), mycophenolate mofetil (p=0.043) and rituximab (p=0.029)-were associated with a slower increase in EDSS in the NMOSD cohort. The immunotherapies and age and disease duration showed similar associations in the NMO-antibody positive subgroup.
Conclusion(s): Treatment with azathioprine, rituximab and mycophenolate mofteil are associated with a slower increase in EDSS in NMOSD and a lower risk of relapses. The risk of relapses declines and accumulation of disability increases with age and disease duration in NMOSD

BACKGROUND:Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of 'post-DMT' relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs. MATERIALS/METHODS/METHODS:Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age ≥ 18 at index DMT start; ≥12 months on index DMT prior to discontinuation; ≥24 months of follow-up post-discontinuation; did not restart DMT for ≥6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for ≥1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. RESULTS:4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNβ preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) - fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. CONCLUSIONS:Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.

Background/UNASSIGNED:Hip and knee replacements for osteoarthritis are established procedures for improving joint pain and function, yet their safety in patients with multiple sclerosis (MS) is unknown. Patients with MS face unique surgical challenges due to underlying neurologic dysfunction. Current literature on arthroplasty in MS is limited to case reports focusing on adverse events. Methods/UNASSIGNED:Of 40 identified patients who underwent hip or knee replacement, 30 had sufficient data for inclusion. We reviewed their medical records and recorded reasons for surgery, age at surgery, MS characteristics, surgical complications, and ambulatory aid status before and after surgery. We supplemented medical record review with questionnaires regarding preoperative and postoperative pain and satisfaction with surgical outcomes. Results/UNASSIGNED:Median follow-up was 26 months. Complications of surgery were reported in ten patients (33%), mostly mild and self-limited, although four patients (13%) required repeated operation. Six patients (20%) reported improvements in ambulatory aid use compared with presurgery baseline, ten (33%) worsened, and 14 (47%) were unchanged. In 20 patients who completed the questionnaire, mean ± SD joint pain scores (on 0-10 scale) decreased from 8.6 ± 2.0 preoperatively to 2.9 ± 2.4 postoperatively (P < .001). Five patients (25%) were free of joint pain at last follow-up. Conclusions/UNASSIGNED:These results suggest that pain reduction is a realistic outcome of total knee or hip arthroplasty in people with MS and that improved functional gait outcomes are possible in some patients. Prospective, multicenter, collaborative studies are needed to optimize selection and improve outcomes in people with MS considering arthroplasty.