Background

White matter (WM) microstructural changes occur in youth with multiple sclerosis (MS) and myelin oligodendrocyte glyoprotein (MOG)-associated disorders. While diffusion tensor imaging has been extensively used to characterize white matter, this method lacks microstructural and pathological specificity. ‘Fixel Based Analysis’ (FBA) statistically estimates changes in diffusion MRI connectivity that is specific to micro and macro-structure. WM damage that leads to less densely packed axons in a fiber bundle causes a decrease in fibre density (FD). If the number of axons is not reduced but occupies less area, then fibre cross-section (FC) will decrease. Last, if the density of axons within a fibre bundle and the area the bundle occupies are reduced, then fibre density and cross-section (FDC) will decrease.

Objectives

To use whole-brain FBA to measure differences in FD, FC, FDC in youth with demyelinating syndromes compared to healthy controls.

Methods

We evaluated group differences in the FBA metrics between 28 typically developing children (17F; age 15.0±2.6y), 19 children with MS (13F; 16.9±1.1y; disease duration (DD)=0.1-11.7y; expanded disability status scale(EDSS):median=1.5,range=0-4.5), and 11 children with MOG (8F;12.1±2.8y; DD=0.5-6.4y;EDSS:m=1.0,r=0-3). Multi-shell diffusion-weighted imaging of the brain was acquired with echo planar imaging on a 3T MRI scanner and was pre-processed to correct for distortions and movement. Whole-brain group FBA was performed on FD, FC and FDC to test differences between groups adjusting for age, sex, total intracranial volume, EDSS and DD (p<0.05, family-wise error (FWE) corrected).

Results

Participants with MS and MOG showed reduced FD, FC and FDC relative to typically developing children (FWE corrected p<0.05). Differences in FD were found within splenium, superior longitudinal fasciculus and optic radiations. MS patients had reduced FDC within the corticospinal tract and cerebellar peduncle compared to MOG patients. In participants with MS and MOG, decreased FD within the brain stem, cerebellar peduncles and corona radiata was associated with increased DD and EDSS.

Conclusions

Our preliminary findings showed that patients with demyelinating disorders display decreased axonal density and fibre bundle size in multiple WM tracts relative to typically developing children, which were related to clinical outcomes (EDSS, DD). These changes were more pronounced in MS compared to MOG participants in selected WM tracts.

Background

Previous comparative effectiveness studies in multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY) on measures of inflammatory disease activity but most studies did not assess long-term disability.

Objectives

To compare long-term disability progression over 5 years (yrs), as assessed by Patient-Determined Disease Steps (PDDS), in NARCOMS registry participants (pts) treated with DMF or FTY.

Methods

The NARCOMS registry is a voluntary self-report registry of people with MS. Pts provide health-related information at enrollment and every 6 months thereafter. We identified pts with RRMS; living in the US; and initiating index DMT (DMF or FTY) from Spring 2011 through Spring 2018. Pts were included if they had ≥1 yr follow-up on index DMT. DMF pts treated with prior FTY, and FTY pts treated with prior DMF, were excluded. We used 1:1 propensity-score matching (PSM) to match FTY to DMF pts. Baseline factors (at time of index DMT initiation) used for PSM were age, disease duration, sex, number of prior DMTs, education, PDDS, cognition score, depression score, relapses in last 6 months, and cardiovascular comorbidities. Time to 6-month confirmed disability progression (≥1-point increase on PDDS sustained for ≥6 months) was estimated using the Kaplan-Meier method and compared using a Cox proportional hazards regression model with robust sandwich estimators. Pts were censored at last follow-up or at the time of DMT discontinuation.

Results

Overall, 689 DMF and 565 FTY pts were included. After PSM, 468 DMF pts were matched with 468 FTY pts. The survey compliance was high in both groups, with >93% of pts in both groups completing ≥50% of surveys while on treatment. Baseline characteristics were well-balanced after PSM, with standardized differences <0.1 for each covariate. Median treatment duration was 3.0 yrs for DMF and 4.0 yrs for FTY. At 5 yrs, 68.3% (95% CI: 62.4-73.5) of DMF pts and 63.3% (95% CI: 59.6-70.1) of FTY pts were free from 6-month confirmed PDDS progression (hazard ratio: 1.01 [95% CI: 0.79-1.28]; p=0.95).

Conclusions

In this propensity-matched analysis of MS pts from the NARCOMS registry, there was no significant difference between DMF and FTY on confirmed disability (PDDS) progression over 5 yrs. These results are consistent with previous studies that have shown similar effectiveness between DMF and FTY on relapse and MRI outcomes.

Supported by: Biogen; NARCOMS is a project of the CMSC

Background

Dimethyl fumarate (DMF) clinical trials excluded relapsing-remitting multiple sclerosis (RRMS) patients aged >55 years (yrs). The limited data on DMF use in this age group evaluated relapses but not disability. Unlike relapses, which often decrease as MS patients age, disability progression often increases.

Objectives

To characterize long-term disability outcomes over 4.5 yrs of DMF treatment in RRMS participants based on age at time of DMF initiation.

Methods

We identified NARCOMS participants (pts) with RRMS, living in the US, and initiating DMF from Fall 2013–Spring 2018 with ≥1 yr follow-up. We dichotomized age at DMF initiation as <55 (younger) and ≥55 yrs (older). Disability was measured using the Patient Determined Disease Steps (PDDS). Time to 6-month confirmed PDDS progression (≥1-point increase) and conversion to SPMS were estimated using the Kaplan-Meier method and compared using a log rank test. Cox proportional hazards regression models were adjusted for sex and initial PDDS level. Pts were censored at last follow-up or DMF discontinuation, whichever came first. Safety data were not collected.

Results

647 RRMS pts initiated DMF. In the younger subgroup (n=351, 54%), median age was 47 yrs, 88% female, and 24% reported a relapse in the last 6 months. In the older subgroup (n=296, 46%), median age was 60 yrs, 82% female, and 22% reported a relapse in the last 6 months. Compared to the younger subgroup, older pts had longer MS disease duration (11 vs 17 yrs, p<0.001) and significantly greater disability at baseline as measured by PDDS. Median treatment duration was 2.5 yrs in younger pts and 2 yrs in older pts. At last follow-up, 283 (81%) younger pts and 236 (80%) older pts remained on DMF. Most pts in both groups were estimated to remain free of disability progression over 4.5 yrs: 64% (95%CI: 57-71) of younger pts vs 74% (95%CI: 67-80) of older pts (p=0.12). Most pts in both subgroups also were estimated to remain free from conversion to SPMS over 4.5 yrs: 90% (95%CI: 85-94) of younger pts vs 86% (95%CI: 79-91) of older pts (p=0.17).

Conclusions

Conclusions: As expected, older pts (≥55 yrs) had significantly longer MS disease duration and higher baseline disability compared with younger pts (<55 yrs). Despite these baseline differences, most pts in both groups remained free of PDDS progression and free from conversion to SPMS over 4.5 yrs of DMF treatment.

Supported by: Biogen; NARCOMS is a project of the CMSC