Background

Minority patients with multiple sclerosis (MS), including those of African ancestry (AA) and Hispanic and Latino ethnicity (HA), have greater disease severity and faster progression than Whites. Minorities are vastly underrepresented in clinical trials, owing to poor access and cultural, economic and other participation barriers. Ocrelizumab (OCR), an anti-CD20 therapy targeting B cells, reduced the rates of disease activity and progression in patients with relapsing MS (RMS) and primary progressive MS in pivotal studies; however, minority participation was <10%.

Objectives

To investigate the efficacy and safety of OCR in AA and HA patients with RMS (2017 McDonald criteria) who meet the US prescribing information criteria in a single-arm Phase IV clinical study designed exclusively to meet the needs of these specific demographic groups.

Methods

An industry-sponsored collaborative approach rooted in minority needs and known knowledge gaps was used.

Results

Key differences between CHIMES (NCT04377555) and other MS trials are as follows:

1. CHIMES was developed in collaboration with patients with MS, patient advocacy groups and investigators.

2. Inclusion criteria allow for ≈150–200 participants with specific, well-controlled, pre-existing comorbidities and baseline creatinine levels within race-specific limits; these factors may disproportionately limit minority patient qualification in other trials.

3. OCR was chosen because of the indications that AA patients with MS may have greater B-cell–mediated pathology, such as a higher CSF IgG index.

4. Written materials will be available in English and Spanish and will be reviewed by a minority patient panel to ensure that they are easy to understand.

5. To enable early results, the primary endpoint is disease activity, defined by the proportion of patients free of protocol-defined events (clinical relapses, CDP or MRI activity) at the end of year 1.

6. All patients may participate in the second-year extension to study disease progression and various biomarker endpoints.

7. One-third of patients will participate in a substudy to assess CSF-specific biomarkers at two time points.

Conclusions

Findings from CHIMES are expected to improve current understanding of MS disease biology, treatment response and clinical trial participation among AA and HA patients with MS, with the ultimate goals of increasing high-quality standard of care to traditionally underserved populations and enhancing equality through clinical research.

Background

Clinical heterogeneity among patients with multiple sclerosis (MS) may be driven by genetic and environmental influences that lead to distinctive MRI features.

Objectives

Our objective was to utilize a cluster analysis to determine the variability of quantitative MRI features among a cohort of MS patients and examine the ability of these imaging features to discriminate patients by clinical disability.

Methods

Ninety-six relapsing remitting MS patients and 7 patients with progressive MS underwent Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) sequence, for myelin water fraction (MWF) analysis, and conventional MRI for measures of lesion volume, cortical thickness and thalamic volume. An agglomerative hierarchical clustering algorithm was implemented using lesion level MRI features selected from a Principal Component Analysis (PCA). The final clusters were selected by implementing a comprehensive validation method based on several unsupervised statistical learning techniques. Matched cluster groups with statistically significant clinical covariates (i.e. age and disease duration) were analyzed based on propensity scores.

Results

A total of 1691 chronic MS lesions were identified among the 103 MS patients. Mean patient age was 44.4 (+/- 11.9) years, disease duration was 10.5 (+/- 8.3) years, and expanded disability status scale (EDSS) was 2.2 (+/- 2.0). PCA demonstrated lesion MWF and volume distributions characterized by 25^th, 50^th and 75^th percentiles account for 87% of the total variability. The hierarchical clustering confirmed two distinct patient clusters. The variables in order of importance were individual lesion median MWF, MWF 25^th, MWF 75^th, volume 75^th percentiles, median individual lesion volume, and total lesion volume (all p-values < 0.000001). Cortical thickness and thalamic volume were significant but less important on cluster discrimination. The clustering MRI features discriminated patients based upon EDSS, p=0.0016 at the time of MRI and maintained EDSS difference at five years (n=72), p=0.0016.

Conclusions

The size and extent of demyelination among individual lesions discriminated MS patients into two MRI lesion-based clusters and was associated with clinical disability. These results suggest an inherent difference among patients with regard to lesion pathology and repair.

Background

Chronic active multiple sclerosis (MS) lesions, characterized by a hyperintense rim (rim+) on quantitative susceptibility mapping (QSM), have been shown to contain iron-enriched, activated microglia and macrophages. QSM is a potential biomarker to monitor treatments directed toward the CNS inflammation. Studies have suggested that dimethyl fumarate (DMF) may reduce the pro-inflammatory innate immune response in the CNS. A comparison to other disease modifying therapies (DMTs) is warranted to evaluate this potential benefit.

Objectives

To determine if dimethyl fumarate (DMF) reduces the iron load, as measured on QSM, in chronic active MS lesions at a greater rate than glatiramer acetate (GA) treatment.

Methods

Sixty-one patients (41 female, 20 male, mean age: 42.1 years +/- 10.9 and EDSS 0.82 +/- 1.2), were considered for this analysis. Fifty-six patients had relapsing-remitting MS and 5 had clinically-isolated syndrome; 37 patients were treated with DMF and 24 with GA. The two treatment groups had similar baseline clinical characteristics; however, DMF patients had less time on treatment as compared to GA (3.86 +/- 1.75 years vs 5.99 +/- 2.67 years, p<0.001). Patients had a QSM scan prior to treatment and a minimum of two on-treatment QSM MRIs. Lesions were classified as rim+ or rim- negative based upon a review of two independent reviewers. To compare longitudinal QSM change in the rim+ lesions among treatment groups, a linear mixed effects model was utilized.

Results

At baseline, patients treated with GA had more QSM rim+ lesions (9.4%) as compared to those starting DMF (4.5%), p=0.0004, however the number of patients having at least one rim+ lesion was similar (16 vs 18 patients) among the treatment groups. DMF patients with rim+ lesions had a longer disease duration as compared to rim+ GA patients (8.15 +/- 6.82 vs 3.55 +/- 4.85 years, p= 0.032). In the subset of patients with QSM rim+ lesions, there was a significantly larger decrease in susceptibility in rim+ lesions with DMF treatment as compared to GA, p< 0.0009. There was minimal reduction of susceptibility in rim- lesions, which was similar among treatment groups; all patients (p=0.92) and QSM rim+ only patients (p=0.11).

Conclusions

This study suggests that DMF reduces the iron load in rim+ MS lesions at a greater rate than GA. These results support QSM to evaluate the effectiveness of various DMTs on the CNS innate immune response in chronic active MS lesions.

Background

The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is a well-established neuropsychological battery to evaluate cognitive changes in patients with Multiple Sclerosis (MS). FreeSurfer has been used to assess neuroanatomical features, including cortical thickness and subcortical volume, as correlates of disease activity. The evaluation of cognitive performance, when combined with FreeSurfer analysis, may offer unique cross-sectional insight into the natural history of MS and the ways in which neurodegeneration interacts with cognition across different stages of disease.

Objectives

This study aims to take a cross-sectional view of a large MS patient cohort and study the relationship between cortical/subcortical measurements and cognitive function across various domains. Its objective is to compare the differences in cortical thickness and subcortical volume in subjects who are cognitively impaired and cognitively unimpaired.

Methods

163 patients with MS underwent both T1-weighted magnetic resonance imaging (MRI) and formal BICAMS testing within three months of one another. FreeSurfer was then used to analyze imaging data. BICAMS includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT). Impairment was based upon published age-matched normative data. Patients had a mean disease duration of 10.5 +/- 7.3 years; mean Expanded Disability Status Scale (EDSS) of 1.3 +/- 1.6; mean age of 42.9 +/- 10.5 years. Multivariate regression analysis was used to compare cortical thickness and subcortical volume in impaired vs.unimpaired subjects.

Results

31, 15 and 38 patients were found to be impaired on SDMT, CVLT, and BVMT testing, respectively. Significant differences were found in multiple subcortical regions among impaired and unimpaired on SDMT (Thalamus; p=0.01) and BVMT (Left/Right Accumbens; p=0.001, p=0.02; Caudate; p=<0.001; Left Cerebellum; p=0.02; Left/Right Hippocampus; p=0.004, p=0.02; Left Pallidum; p=0.01; Left/Right Putamen; p=0.02, p=0.004; Right Amygdala; p=0.02; Right Thalamus; p=0.004). Impairment on SDMT was associated with differences in caudal anterior cingulate cortex (p= 0.001) and entorhinal cortex (p=0.003) and BVMT impairment was associated with thinning in temporal lobe regions (Right Bank of Superior Temporal Lobe; p=0.008; Right Fusiform; p=0.02). SDMT, CVLT, BVMT were all associated with differences in various occipital lobe regions. No significant differences were found when looking at the four anatomic lobes in their entirety.

Conclusions

Our results show associations between impaired performance on certain neuropsychological tests and regional cortical thinning and subcortical volume loss in what is the largest known cohort to date. These findings could shed light on unique and overlapping neuroanatomical substrates underlying different cognitive processes in MS.