9th Joint ECTRIMS-ACTRIMS meeting – 11-13 October 2023

The following summarizes some of the highlights from Day 1 of ECTRIMS-ACTRIMS 2023.

October 13 Edition
October 12 Edition

Evaluating drug discontinuation
Biomarkers of progression in PPMS
Impact of obesity on MS
Natalizumab: treatment prolonged with extended-interval dosing
CNS effects of ofatumumab
Clinical tip of the day

CONGRESS HIGHLIGHTS – WEDNESDAY EDITION

Evaluating drug discontinuation
DISCOMS was a phase IV noninferiority study (N=259) examining DMT discontinuation in MS patients aged >55 years with no recent disease activity (no relapses in 5 years, no new MRI lesions in 3 years) (Corboy et al. Lancet Neurol 2023;22:568-577). At 22 months, relapses were more common in patients discontinuing treatment vs. remaining on therapy (12.2% vs. 4.7%) but results were inconclusive since the treatment difference (7.5%) did not meet the non-inferiority cut-off of 8%. The extension phase enrolled completers with no disease activity during the initial study (n=76) (Corboy et al. ECTRIMS/ACTRIMS 2023;P309). Overall, there were no relapses in either group and new MRI lesions were rare. In this cohort, there was no difference in time to event (disease activity) with drug discontinuation vs. continuation.

Biomarkers of progression in PPMS
A finding of a high level of glial fibrillary acidic protein (GFAP) and a low level of serum neurofilament-light (NfL) is highly predictive of disability progression in PPMS patients, according to the German EmBioProMS (EMerging blood BIOmarkers in PROgressive Multiple
Sclerosis) study (Abdelhak et al. ECTRIMS/ACTRIMS 2023;P632). Blood samples were obtained for 243 PPMS or SPMS patients; median follow-up was 25.1 months. Over the course of 338 visits, 111 progression events were recorded. Most progression events were documented using the T25FW, followed by the 9HPT and EDSS. Both GFAP and NfL were elevated at baseline. GFAP and NfL levels that were elevated three- and 1.5-fold, respectively, above normal values (Z score 0) were associated with a 2- to 3-fold higher risk of progression in PPMS patients. The highest risk of disability progression was seen in PPMS patients with high GFAP and low NfL levels, which may have indicated a neurodegenerative subgroup with nonactive disease.

Impact of obesity on MS
Recent studies have suggested that obese individuals diagnosed with MS experience more rapid disability progression and worse outcomes, although obesity does not appear to be associated with increased disease activity (relapses, Gd+ lesions, T2 lesion burden) (Lutfullin et al. J Neurol Neurosurg Psychiatry 2023;94:57-61). However, a new study has reported that obesity is associated with more rapid progression of physical disability although the effect is small; a more significant impact may be seen on the rate of cognitive disability (Wu et al. ECTRIMS/ACTRIMS 2023;O110). The study analysed Swedish MS registry data (N=3249) stratified by body-mass index; mean age was 37.8 years. During the observation period, obesity was associated with a slightly more rapid increase in EDSS score (0.022 points/year), and a 1.43-fold higher risk of reaching EDSS 3.0. Moreover, obese MS patients had a higher risk of worsening cognitive disability (hazard ratio 1.47) compared to non-obese patients.

A separate study examined the impact of obesity-associated hyperinsulinemia on autoimmunity (Correale et al. ECTRIMS/ACTRIMS 2023;P540). The rationale was that insulin promotes glucose uptake via the protein kinase B (AKT) pathway, which also regulates the development of Tregs (CD4+CD25+FoxP3+) (reviewed in Saige et al. J Leukoc Biol 2018; epublished January 22, 2018). The study compared MS patients with and without obesity and healthy controls (N=90). Serum insulin levels were higher in obese MS patients compared to the other two groups. Insulin levels were associated with greater AKT induction in Tregs; however, higher AKT activity was associated with suppression of IL-10 by Tregs and reduced expression of FoxP3. Thus, obesity-associated hyperinsulinemia appears to reduce the formation of Tregs from CD4+ T cells and may contribute to Treg dysfunction.

Natalizumab: treatment prolonged with extended-interval dosing
A retrospective study of patients on natalizumab enrolled in the Canadian Biogen One patient support program found that the mean time on therapy was significantly longer (289 vs. 178 weeks) for those receiving extended-interval dosing (EID) dosing compared to standard dosing (Morrow et al. ECTRIMS/ACTRIMS 2023;P694). The study included 4844 of 6149 patients enrolled in the program. Patients enrolled in 2021 were younger (mean age 37.5 vs. 39.1 years) and with a shorter duration of MS (mean 6.0 vs. 9.1 years) compared to those enrolled in 2006. The mean duration of natalizumab exposure was 34.2 months prior to 2016 vs. 43.5 months in 2021. At baseline, 54% of patients (n=2468) were JCV Ab-negative; 26% of JCV-negative patients changed serostatus over a mean follow-up of 44.5 months.

CNS effects of ofatumumab
A small imaging study examined the potential effect of the anti-CD20 MAb ofatumumab on microglial activation and brain iron in RMS patients (Singhal et al. ECTRIMS/ACTRIMS 2023;P179). The technique employed was radiolabelled PET imaging ([F-18]PBR06), which uses translocator protein (TSPO) binding as a marker of microglial activation (Singhal et al. Semin Neurol 2017;37:546-557; presented at AAN 2018;P3.386). Quantitative susceptibility mapping (QSM) was used to measure brain iron. At nine months following ofatumumab initiation, there was a reduction in microglial activation in cortical grey matter but not in normal-appearing white matter (NAWM) or thalamic regions of interest. A decrease in brain iron was also observed in cortical grey matter and NAWM. Treatment was associated with a significant reduction from baseline in serum NfL levels.

Clinical tip of the day
An MSBase study reported that pregnancy does prolong the time to EDSS 3.0 – with an important caveat (Zhu et al. ECTRIMS/ACTRIMS 2023;P463). A beneficial effect was limited to women with MS for <5 years who became pregnant before age 30. The impact of pregnancy on the MS clinical course declined over time and was no longer significant after age 30.

October 13 Edition
October 12 Edition