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HT04.03 - Presentation 03 - Cortical atrophy in multiple sclerosis may start at puberty
Decreased gray matter (GM) volumes have been shown at the diagnosis of multiple sclerosis (MS), suggestive of early neurodegeneration processes preceding clinical symptoms. The onset and progression rate of atrophy in early stages and across large time spans in MS is still, however, uncertain.
To analyze cortical atrophy rates in relation to the patient age vs. disease duration, to find a possible impact of age-at-onset on atrophy progression and to retropolate the time of the brain atrophy onset, based on the progression rate and trajectories.
Standardized high-resolution brain volumetric imaging was performed in the Stockholm Prospective Assessment of MS (StopMS) study. A total of 1085 MS patients (age: 11-79 years, disease duration: 0-48 years) were included and 3642 brain MRI scans were performed. FSL-SIENAX was used to evaluate the normalized cortical GM volume and further analyzed using R-libraries. Cortical atrophy rates were assessed in relation to age and disease duration respectively and stratified into five age-at-onset subgroups: <20, 20-30, 30-40, 40-50, >50 years. Locally estimated scatterplot smoothing - LOESS and linear regressions were used to calculate atrophy rates for each subgroup for the first, last and all MRI scans performed per patient (range 1-14 scans per person, median 3 scans) between the ages 17 and 60 years, and duration 0-40 years. Demographic and clinical data were available from the Swedish MS Registry.
Cortical atrophy had a clearly linear progression with patient age. At the group level, the normalized cortical GM volume decreased by 3.1 ml/year. The corresponding annual cortical atrophy rates were 0.43% at age 17 and 0.53% at age 60. Patients with later onset started with lower cortical volume, following a similar linear age trajectory as patients with earlier onset. Similar findings were found for both sexes and all MS subtypes. Primary progressive MS patients, older at diagnosis, had the correspondingly lower cortical volume at their time of diagnosis. Retropolation of cortical atrophy trajectory along the linear age-related slopes to normative values suggested that MS atrophy can possibly start as early as at the age of 13 (time of puberty). Similar GM volume analyses vs. disease duration (instead of age) showed separate atrophy trajectories, where each age-at-onset subgroup started with 350 ml difference in volume at the time of onset and followed its own quasi-linear trajectory. Early age-at-onset subgroups had a higher atrophy rate with disease duration and a late age-at-onset subgroups had the lower rates.
Cortical atrophy progresses linearly from around the time of puberty, i.e. typically before the first reported MS symptom and appears largely independent of reported time of MS onset, diagnosis, or a subtype. Assessments of neurodegeneration in MS should preferably be analyzed in relation to the patient's age rather than the disease duration.
Author Of 1 Presentation
P0239 - Temelimab for prevention of neurodegeneration: preclinical safety profile and design of the ProTEct-MS (temelimab following rituximab in RMS) study (ID 1803)
Background: The envelope protein of the human endogenous retrovirus type W (HERV-W ENV) is expressed in chronic active MS lesions. Preclinical models have shown that HERV-W ENV activates microglia, prevents maturation of oligodendrocyte precursor cells, and leads to neuronal death. Following the effects of a B-cell depleting, anti-inflammatory therapy, rituximab (RTX), with temelimab (TML), a humanized, IgG4-κ monoclonal antibody against HERV-W ENV represents a novel therapeutic approach against neurodegenerative features of MS.
Objective: To present safety preclinical results on the interaction of RTX and TML, and the trial design of the ProTEct-MS study.
Design/Methods: Interactions between RTX and TML were studied in vitro in high density-peripheral blood mononuclear cells (PBMCs) and ex-vivo in a whole blood loop system from fresh human blood.
ProTEct-MS is a randomized, double-blind, placebo controlled, parallel group study. Enrolment commenced in 2020/6 and will be completed in 2020/12. Patients with RMS (2017 McDonald criteria) (N=40) being previously treated for ³12 months with RTX are randomized (1:1:1:1) to monthly iv TML (18, 36 or 54mg/kg) and placebo for 48 weeks.
Eligibility criteria: age 18-55 yrs, Expanded Disability Status Scale (EDSS) of 2.5-5.5 at screening; clinical worsening in ³1 neurological domain as assessed by EDSS, 6MWT or T25FW, or cognitive functioning as assessed by SDMT over the last year.
Primary objective: assessment of safety and tolerability of TML
Secondary outcome measures: MRI: change of brain atrophy, lesion volume and magnetization transfer ratio
Results: Co-administration of TML with RTX was overall comparable to vehicle for all blood parameters assessed including cytokine levels of all five donors tested in both in vitro and ex-vivo assays. Co-administration of TML with RTX did not affect the functionality profile of either compound. By September 2020, 25% of patients are expected to be randomized, providing baseline clinical and MRI characteristics.
Conclusions: Preclinical safety experiments of the drug combination showed no evidence against the use of TML following RTX in humans. ProTEct-MS study patients represent a RMS cohort with progression in absence of relapse activity (PIRA,) i.e. whose present clinical condition is stable under RTX therapy, enabling TML's effects on attenuating mechanisms of progression to be measured without interference by acute inflammatory activity.