Abstract

Background: Multiple sclerosis is characterized by both neuroinflammation and accelerated brain atrophy. These two processes can be quantified by MRI, are at least partially independent, and have different underlying pathological mechanisms. MicroRNA (miRNA) have previously shown strong ties to various neurological disease processes, and have potential as biomarkers in MS.

Objectives: To classify and immunologically characterize persons with MS based on serum miRNA profiles in conjunction with MRI phenotypes, as defined by relative burden of cerebral T2-hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF).

Methods: Cerebral T2LV and BPF were retrospectively quantified from 1.5T MRI, and used to define the following MRI phenotypes. Type I: low T2LV, low atrophy; type II: high T2LV, low atrophy; type III: low T2LV, high atrophy; type IV: high T2LV, high atrophy, in a large cross-sectional cohort (n = 1,088) and a subset with 5-year longitudinal follow-up (n = 153). Serum miRNAs were assessed on a third MS cohort with 2-year MRI phenotype stability (n = 98). A proportional odds logistic regression model was used to determine significant associations been MRI features and miRNA expression.

Results: One-third of the patients showed dissociation between lesion burden and atrophy severity as defined by MRI phenotypes II or III. At 5-year follow-up, all phenotypes showed increased atrophy (p < 0.001), disproportionally in type II (BPF −2.28%). Only type IV experienced significantly worse neurological disability scores. Types I and II had a 5-year MRI phenotype conversion rate of 33% and 46%, whereas III and IV had >90% stability. Type II switched primarily to IV (91%); type I switched primarily to II (47%) or III (37%). Baseline higher age (p = 0.006) and lower BPF (p < 0.001) predicted 5-year phenotype conversion. MicroRNA analysis revealed sixteen miRNA differentially expressed (p < 0.05, uncorrected) between the four phenotypes. Each phenotype demonstrated a distinct miRNA signature. Biological interpretation of these miRNA suggest a role for blood-brain barrier pathology. miR-22-3p, miR-361-5p, and miR-345-5p were the most valid differentiators.

Conclusions: MRI-defined MS phenotypes show high conversion rates characterized by relentless brain atrophy with or without ongoing inflammation, and results support the partial independence of these two features. Differentially expressed serum microRNA for the MRI phenotypes implicates the blood-brain barrier as an important mechanism determining pathological course. MicroRNA are promising as biomarkers in MS but require significant further verification and methodological standardization.

Background

Additional data on alemtuzumab use including clinical, imaging and safety outcomes in a real-world setting can improve patient care.

Objectives

To examine clinical, imaging and safety outcomes in relapsing multiple sclerosis (MS) patients who received at least 2 courses of alemtuzumab.

Methods

This retrospective, single-center study included patients treated with at least 2 courses of alemtuzumab and at least 12 months of follow-up. Demographic, clinical (annualized relapse rate; disability progression); imaging characteristics (brain and spine MRI); previous treatment; co-morbidities and adverse events were analyzed. Patient data for 2 years prior to course 1 (index date) and for up to 4 years after initiation of alemtuzumab was available for all patients.

Results

74 patients were included. Mean age (SD) at baseline was 41.8 (9.9), diagnosis duration 11.5 (7.8) years. 33 patients needed help with ambulation; of which 11 were wheelchair-bound. 45% of patients switched from natalizumab and 23% from fingolimod primarily due to MS worsening. After Alemtuzumab treatment, ARR was significantly decreased from 1.231 (1-year pre-) to 0.392 (1-year post-) index date (P < 0.0001) and to 0.313, 0.240 and 0.291 during each of following 3 years respectively. Comparing one year prior to and 2-years post- treatment: more patients had stable spinal cord MRI (94.3% vs 62.5%) and fewer showed worsening (37.5% vs 5.7%) (p = 0.0017). On brain MRI, more patients were stable (87.7% vs. 52.1%) and fewer patients showed worsening (48.0% vs. 9.6%) (p<0.0001). On disability, 69% of patients remained stable; 3 of 11 wheelchair-bound patients became ambulatory. Safety outcomes will be available for presentation.

Conclusions

This real-world data suggests alemtuzumab is clinically and radiographically safe and effective in a wide spectrum of MS patients including those with severe disability, longer disease duration and multiple comorbidities. Long term follow-up of this cohort will help assess the clinical efficacy of alemtuzumab in a real-world setting.