Background

Serum neurofilament light-chain (sNfL) is associated with disease activity and tissue damage, predicts long-term outcomes, and is reduced by disease-modifying therapies in RRMS patients.

Objectives

In a post hoc analysis, determine sNfL differences from baseline (BL) to 48 months and associations with long-term clinical outcomes in patients treated with intramuscular (IM) interferon (IFN) beta-1a, glatiramer acetate (GA), or both therapies (IFN+GA).

Methods

CombiRx was a placebo (PLB)-controlled double-blind phase 3 trial in treatment-naive RRMS patients randomized to IM IFN beta-1a 30 µg weekly+PLB, GA 20 mg/mL daily+PLB, or IFN+GA treatment for up to 7 years. Samples for biomarker analysis were collected at BL, 6, 12, 36, and 48 months from volunteers for a substudy offered in most sites. Relapses and Expanded Disability Status Scale (EDSS) scores were collected every 3 months. A Simoa Human Neurology 4-Plex A assay analysed sNfL levels. A linear mixed model compared sNfL values over time adjusted for BL EDSS, age, sex and body mass index (BMI). A Cox regression model with the same covariates analysed BL sNfL as a predictor of relapse.

Results

Samples were collected from 159 IFN, 172 GA, and 344 IFN+GA patients. BL characteristics were generally well balanced, including mean age, sex, mean BMI, mean time since symptom and diagnosis onset, and mean EDSS scores. Significant reductions relative to BL in sNfL levels were seen at 6, 12 and 36 months in the IFN, GA, and IFN+GA treatment groups. BL sNfL ≥16 pg/mL significantly predicted relapse within 90 days (hazard ratio [HR]: 2.25, P=0.0041), 180 days (HR: 1.67, P=0.0130) and 1 year from BL (HR: 1.40, P=0.0435), but not over the entire study duration (HR: 1.08, P=0.5596). In patients with BL sNfL ≥16 pg/mL and ≥1 BL gadolinium-enhancing (Gd+) lesion, a significantly higher percentage (16.8%) relapsed within 90 days than in patients with BL sNfL ≥16 pg/mL and no BL Gd+ lesions (9.2%), or BL sNfL <16 pg/mL with (7.3%) or without BL Gd+ lesions (6.7%) (P=0.0051).

Conclusions

Treatment with IFN, GA, and IFN+GA significantly reduced sNfL levels within 6 months and was maintained over 36 months. Results suggest that BL sNfL levels predict relapses within 1 year, and that the combination of lesion activity and sNfL is a stronger predictor of relapse than either one alone.

This analysis was funded by Biogen. Biogen also funded the writing support for this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

Background

Depression and anxiety have increased prevalence in multiple sclerosis (MS). There are limited studies on associations of depression and anxiety with MS disease characteristics.

Objectives

The aim of the study is to identify and quantify associations of depression and anxiety with MS disease activity and disability.

Methods

The study population included a prospective cohort of 1008 treatment-naïve participants with relapsing-remitting (RR) MS enrolled in the CombiRx trial. Entrance criteria included at least 2 relapses in the prior 2 years. Covariate adjusted linear regression analyses were conducted to determine associations and adjusted R-squared (R2) between baseline scores on three components of the Multiple Sclerosis Quality of Life Index (MSQLI): the Mental Health Inventory (MHI), Depression Subscale (MHD), and Anxiety Subscale (MHA), where lower scores indicated more severe symptoms on each component of the MSQLI subscale; with outcomes of baseline MS disease characteristics including Expanded Disability Status Scale (EDSS) and total MRI lesion volume (T1+T2). Kruskal-Wallace comparison was used to assess prior relapse frequency (0, 1-2, and 3 or more in prior 12 months) and median MSQLI measures.

Results

Lower EDSS scores were associated with higher MHI scores (β = -0.31, R² = 0.1274, p <0.0001), higher MHA scores (β = -0.21, R² = 0.1060, p <0.0001), and higher MHD (β = -0.22, R² = 0.1096, p <0.0001), when adjusted for age and sex at baseline. Baseline MHA score was modestly associated with relapse frequency (p =0.043), with a median rank MHA score of 5 for 0 relapses, 4.6 for 1-2 relapses, and 4.6 for ≥3 relapses. Components of the MSQLI were not associated with MRI lesion volume.

Conclusions

Depression and anxiety in MS are associated with increased baseline EDSS disability. Of the three measures, only anxiety was associated with higher baseline relapse frequency. A follow-up analysis is planned to examine associations of depression and anxiety on longitudinal MS disease outcomes in the trial cohort.

Background

The thalamus and the putamen, highly-connected brain areas (hubs), are vulnerable to MS-induced atrophy. Here we investigate if white matter (WM) tracts that pass through hubs have different susceptibility to MS pathology, due to anterograde and retrograde neurodegeneration, compared to tracts do not pass through these hubs. We use the apparent intra-axonal volume fraction (V_ax) derived from the multi-compartment diffusion MRI spherical mean technique (SMT) as well as the neurite density index (NDI) and isotropic volume fraction (IVF) derived from the neurite orientation dispersion and density imaging (NODDI) coupled with high-resolution tractography to assess the degree of tract-specific axonal integrity.

Objectives

(1) To compare tract-specific lesion burden, V_ax, NDI and IVF between WM tracts that overlap with either the thalamus or the putamen (hub+ tracts) and those that do not (hub- tracts); and (2) to assess the relationship between these MRI metrics and those of physical impairment, as measured by the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk test (T25FW).

Methods

EIghteen patients underwent 3T MRI inclusive of T1- and T2-weighted sequences, SMT and NODDI. Using probabilistic tractography, we reconstructed 49 WM tracts, 12 hub+ tracts and 37 hub- tracts. Using T-tests, we compared the following MRI metrics between hub+ and hub- tracts: T1 and T2 lesion burden (calculated as percentage of tracts occupied by T1 and T2 lesions) as well as whole tract and normal-appearing WM (NAWM) average NDI, IVF and V_ax values. Spearman correlation assessed the relationship between these MRI metrics and those of clinical impairment.

Results

Hub+ tracts had a lower mean %T1 lesions (0.86 vs. 1.99) and %T2 lesions (2.90 vs. 5.42), as well as higher whole tract NDI (0.61 vs. 0.57), NAWM NDI (0.61 vs. 0.58), whole tract V_ax (0.49 vs 0.44) and NAWM Vax (0.50 vs. 0.44), all significant at the p<0.001 level. Stronger correlations were seen between clinical measures and hub+ tracts compared to hub- tracts, with the strongest correlation for %T1 lesions and the T25FW (r= -0.59, p<0.0001).

Conclusions

WM tracts that overlap with the thalamus and the putamen have a higher degree of axonal integrity and lower lesional burden, suggesting a protective role of hubs. However, given the ramifications of disease present at the level of hub+ tracts, disease here retains a major impact on disability. If confirmed, our data suggest the role of disease location in relation to hubs as guidance for treatment personalization, considering more aggressive approaches for patients presenting with MRI changes in hub+ fiber tracks.

Background

Serum neurofilament light-chain (sNfL) is associated with disease activity and tissue damage, predicts long-term outcomes, and is reduced by disease-modifying therapies in RRMS patients.

Objectives

In a post hoc analysis, determine sNfL differences from baseline (BL) to 48 months and associations with long-term clinical outcomes in patients treated with intramuscular (IM) interferon (IFN) beta-1a, glatiramer acetate (GA), or both therapies (IFN+GA).

Methods

CombiRx was a placebo (PLB)-controlled double-blind phase 3 trial in treatment-naive RRMS patients randomized to IM IFN beta-1a 30 µg weekly+PLB, GA 20 mg/mL daily+PLB, or IFN+GA treatment for up to 7 years. Samples for biomarker analysis were collected at BL, 6, 12, 36, and 48 months from volunteers for a substudy offered in most sites. Relapses and Expanded Disability Status Scale (EDSS) scores were collected every 3 months. A Simoa Human Neurology 4-Plex A assay analysed sNfL levels. A linear mixed model compared sNfL values over time adjusted for BL EDSS, age, sex and body mass index (BMI). A Cox regression model with the same covariates analysed BL sNfL as a predictor of relapse.

Results

Samples were collected from 159 IFN, 172 GA, and 344 IFN+GA patients. BL characteristics were generally well balanced, including mean age, sex, mean BMI, mean time since symptom and diagnosis onset, and mean EDSS scores. Significant reductions relative to BL in sNfL levels were seen at 6, 12 and 36 months in the IFN, GA, and IFN+GA treatment groups. BL sNfL ≥16 pg/mL significantly predicted relapse within 90 days (hazard ratio [HR]: 2.25, P=0.0041), 180 days (HR: 1.67, P=0.0130) and 1 year from BL (HR: 1.40, P=0.0435), but not over the entire study duration (HR: 1.08, P=0.5596). In patients with BL sNfL ≥16 pg/mL and ≥1 BL gadolinium-enhancing (Gd+) lesion, a significantly higher percentage (16.8%) relapsed within 90 days than in patients with BL sNfL ≥16 pg/mL and no BL Gd+ lesions (9.2%), or BL sNfL <16 pg/mL with (7.3%) or without BL Gd+ lesions (6.7%) (P=0.0051).

Conclusions

Treatment with IFN, GA, and IFN+GA significantly reduced sNfL levels within 6 months and was maintained over 36 months. Results suggest that BL sNfL levels predict relapses within 1 year, and that the combination of lesion activity and sNfL is a stronger predictor of relapse than either one alone.

This analysis was funded by Biogen. Biogen also funded the writing support for this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).