Background

Natalizumab extended interval dosing (EID) is associated with lower risk of progressive multifocal leukoencephalopathy than every-4-week standard interval dosing (SID). Independent real-world (RW) studies suggest that natalizumab effectiveness is maintained in patients who switch from SID to EID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a learning health system comprised of a collaborative network of healthcare institutions that provides access to RW clinical and MRI data collected using standardized acquisition protocols.

Objectives

Compare the effectiveness of natalizumab EID and SID using quantitative MRI metrics from highly standardized RW images in MS PATHS.

Methods

An MRI segment was defined as 2 MRI acquisitions and associated interval duration. MS PATHS patients with ≥1 MRI segment, ≥2 infusion cycles (infusion interval >21 days and ≤84 days), and complete covariate information were eligible. MRI segments with average infusion cycle (AIC) ≤35 days and >35 days were defined as SID and EID, respectively. For each MRI segment, new T2 lesions and changes in T2 lesion volume (T2LV) and brain parenchymal fraction (BPF) were compared for SID and EID using inverse probability weighting (IPW) with logistic regression and robust linear regression.

Results

IPW analysis included 327 SID patients (596 MRI segments) and 67 EID patients (85 MRI segments). The mean AIC for SID was 29.5 (standard deviation [SD] 1.8) days and 40.8 (4.9) days for EID. Mean MRI segment duration for SID and EID was 9.7 (SD 5.5) and 9.6 (5.3) months, respectively. Proportions of patients with no new T2 lesions were similar for the SID and EID groups (75.6% vs 75.3%; adjusted odds ratio for 0 vs ≥1 lesion=0.967 [95% CI 0.500, 1.871]; P=0.921). SID and EID patients did not differ significantly in adjusted T2LV change (−0.070 [95% CI −0.129, 0.111] mL vs 0.022 [−0.132, 0.180] mL; P=0.233) or BPF change (−0.1222% [95% CI −0.1524%, −0.0921%] vs −0.1442% [−0.2234%, −0.0649%]; P=0.617).

Conclusions

MRI activity was low in SID and EID MS PATHS patients, and there were no significant differences in MRI outcomes between the 2 groups. These results confirm and extend previous RW studies of natalizumab EID effectiveness. Study limitations include modest EID sample size and potential channeling bias. The ongoing phase 3b randomized trial NOVA (clinicaltrials.gov NCT03689972) will further evaluate the effectiveness of natalizumab EID versus SID.

MS PATHS is supported by Biogen.

Background

Background: Multiple sclerosis (MS) incidence in Hispanic Americans (HA) is increasing, highlighting the need to understand disease features and clinical course trends among this subpopulation.

Objectives

Objective: To compare demographic features and clinical characteristics of a large population of HA and non-Hispanic Caucasian Americans (NHCA) with MS.

Methods

Methods: MS PATHS is a network of MS Centers in the United States (n=7) and Europe (n=3) contributing standardized data acquired during routine care. US-based MS PATHS participants who self-reported as HA (irrespective of race) or as NHCA, and compared the groups according to demographic (sex, years of education, smoking status, BMI, employment, and insurance status), MS clinical (self-reported disability via Patient Determined Disease Steps [PDDS]), and neuro-performance (via the MS Performance Test (MSPT): walking, manual dexterity, and processing speed) features. Odds ratios and mean differences for PDDS and neuro-performance outcomes were adjusted for age, sex, disease duration and subtype, smoking status, BMI, insurance status, employment status, and years of education. Z-score is compared to a representative healthy population.

Results

Results: Compared to NHCA (n=9003), HA (n=609) had earlier MS symptom onset (mean 28.6y [SD:10.7y] vs 33.6y [11.3y]; p<0.001) and younger age at diagnosis (31.6y [10.9y] vs 36.6y [10.9y]; p<0.001). HA were more likely to have mild disability by the PDDS, compared to NHCA (OR 0.62, 95% CI [-0.89, -0.06], p=0.02). However, HA had worse performance on both manual dexterity times (z score: 0.31 [0.14, 0.47], p<0.001), and cognitive processing speed score (# correct: 0.37 [0.27-0.47], p<0.0001). 25-foot walking speed was not different between the groups (z score:0.09 [-0.23,0.41], p=0.56).

Conclusions

Conclusion: Using standardized data collection in this large MS sample, HA compared to NHCA patients were found to have younger age of onset and diagnosis and higher levels of cognitive and manual dexterity slowing. However, HA were less likely to rate themselves with severe disability on the PDDS. As the groups did not differ in walking speed, this may reflect the scale relatively weighting ambulation over other functions or other language/cultural differences.

Background

Fatigue is among the most frequent and disabling symptoms in relapsing multiple sclerosis (RMS) patients. A greater understanding of MS fatigue and associated, MS-specific patient reported outcomes tools to characterize fatigue and its impact would improve patient care.

Objectives

To measure MS fatigue and its impact on daily life in a real-world population using a survey including the RMS-specific Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS).

Methods

This is an ongoing noninterventional prospective study of ambulatory adult RMS patients recruited across the USA via an online survey. Participants completed demographic and clinical questionnaires including disease history and status, sleep, social and emotional functioning, along with the FSIQ-RMS, administered daily for 7 days. The FSIQ-RMS addresses the symptoms of fatigue, rated for severity based on the mean of the 7-day symptom assessment, and corresponding impacts of fatigue on 3 domains: physical, cognitive/emotional, and coping. The FSIQ-RMS scores range from 0-100 (higher score indicates greater severity). Data were collected via an online patient platform (Carenity).

Results

A total of 142 RMS patients completed the 7-day assessment: mean age: 43.5 yrs; 87% women; mean age at diagnosis: 33.2 yrs. Fatigue levels were severe and had high impact with a mean score during the 7-day period of 59.5 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 45.1, 44.9 and 50.6 (physical, cognitive/emotional, and coping). The most impactful symptom on daily functioning was walking difficulties, followed by fatigue. A majority of patients (56%) experienced fatigue before MS diagnosis. Most patients (72%) were not currently relapsing and had a mean fatigue symptom domain score of 56.2 (vs 68 in relapsing patients). Those with lower disability tended to rate fatigue as the most impactful symptom on daily life. A majority of patients were not depressed (56%) nor reported a sleep disorder (72%), yet still reported mean fatigue symptom domain scores of 53.7, 58.1 respectively (vs 67, 63.3 in those with depression or sleep disorder). Heat exposure (82%) was the most common triggering factor for fatigue.

Conclusions

In this survey including the novel RMS specific FSIQ-RMS, fatigue occurred in most MS patients and had an influence on daily functioning. The FSIQ-RMS measures fatigue symptoms and impacts, which are relevant and meaningful to patients.

Background

There is increasing evidence that upper extremity (UE) motor functioning, measured by speeded pegboard completion, correlates with cognitive functioning in multiple sclerosis (MS). To date, studies have characterized this correlation with single assessment points in cross-sectional studies. However, to be validated as a behavioral biomarker of cognition, pegboard completion should also reflect change in cognitive functioning over time.

Objectives

To characterize changing of pegboard completion and cognitive functioning at baseline and following cognitive remediation program.

Methods

In this large RCT of n=135, n=74 participants with MS (EDSS 0-8, relapsing-remitting and progressive subtypes) completed an adaptive cognitive remediation program (60 hours x 12 weeks) that led to a significant improvement in cognitive functioning compared to a control condition (n=61). Cognitive functioning was assessed by a composite score from a comprehensive battery of neuropsychological measures, while UE functioning was assessed by the 9-Hole Peg Test (9-HPT). Study outcomes were evaluated at baseline and treatment end.

Results

Participants in the active condition (median EDSS 3.5, age 48 ± 13 years, 67.5% female; 69% relapsing-remitting) significantly improved in cognitive functioning (composite neuropsychological z-score: -0.77 vs. -0.68, p<0.001) and in the 9-HPT completion for the dominant hand (9-HPT z-score: -4.1 vs -3.3, p=0.013). Within the active condition group, only those with relapsing-remitting subtype were found to have a significant improvement in the completion time of 9-HPT (dominant hand 9-HPT z-score: -3.4 vs. -2.4, p<0.001; non-dominant hand 9-HPT z-score: -3.0 vs. -2.5, p=0.04). In the control condition, where no significant improvement in cognitive functioning was found, there was not an improvement in the 9-HPT completion.

Conclusions

Routine pegboard completion is a quick and efficient measure of both cognitive and fine motor involvement in MS at one point in time and in response to change in cognitive functioning. However, this relation is specific to those with relapsing-remitting subtype, likely due to higher motor impairment in those with progressive disease.

Background

Fatigue is a common and often debilitating symptom of multiple sclerosis (MS) that remains without an effective treatment. Noninvasive brain stimulation with transcranial direct current stimulation (tDCS) is a promising therapeutic approach with controlled clinical trials demonstrating its near-term benefit in reducing MS fatigue. However, the persisting benefit of treatment has not yet been characterized.

Objectives

To test whether there is persisting benefit for the treatment of MS-related fatigue with noninvasive brain stimulation using tDCS.

Methods

As part of a larger study participants with MS-related fatigue completed the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS) at baseline and following 20 daily at-home remotely supervised or RS-tDCS sessions (open-label, 20min x 2.0mA, anode over left DLPFC and cathode over right DLPFC) paired with computerized cognitive training (BrainHQ). Assessments were repeated at 3-months post-treatment.

Results

Participants were n=17 with MS, mean age 49.1 ± 10.8, EDSS median 5.0 (0-7) and clinically significant fatigue at baseline (FSS= 51.2 ± 10.4). Consistent with prior studies, there was a significant reduction in fatigue following 20 daily treatment sessions (51.6 ± 15.5 vs. 37.9 ± 13.1, mean difference -13.7, p= 0.007). Statistically significant reductions in fatigue were further seen across all MFIS sub scores: physical (24.1 ± 7.3 vs. 19.0 ± 7.55, p= 0.024), cognitive (22.5 ± 9.1 vs. 14.9 ± 7.8, p= 0.004), and psychological/social (5.0 ± 2.0 vs. 4.0 ± 1.6, p= 0.033). At three months post treatment, fatigue benefit persisted (51.6 ± 15.5 vs. 41.4 ± 11.7, mean difference -10.2, p= 0.02). Statistically significant reductions in fatigue were maintained 3-months post-treatment in the social (p= 0.004) and physical (p= 0.02) MFIS sub scores.

Conclusions

A period of repeated daily treatment with left anodal dorsolateral prefrontal cortex tDCS can lead to persisting reductions in MS-related fatigue 3-months post treatment.