Brigham and Women’s Hospital

Author Of 2 Presentations

Imaging Oral Presentation

HT05.03 - Presentation 03 - 7T MRI cerebral leptomeningeal enhancement predicts gray and white matter lesion accumulation one year later in relapsing-remitting multiple sclerosis

Speakers
Presentation Number
HT05.03
Presentation Topic
Imaging
Lecture Time
10:39 - 10:51

Abstract

Background

We recently showed that 7T MRI leptomeningeal enhancement (LME) is common in relapsing-remitting multiple sclerosis (RRMS) and is related to gray matter (cortical/thalamic) and white matter (WMLs) lesions.

Objectives

To investigate the dynamics of LME longitudinal change and relationship to subsequent lesion accumulation using 7T MRI.

Methods

25 RRMS subjects [age 44.5±11.2 years (mean±SD), 68% women, Expanded Disability Status Scale (EDSS) 2.0±1.5, 92% on disease-modifying therapy-DMT] and 12 healthy controls (HC) underwent brain 3D MP2RAGE and FLAIR 7T MRI with 0.7 mm3 voxels at baseline and ~1 year. Gadolinium-enhanced 3D-FLAIR was evaluated for LME. WMLs, cortical lesions (CLs) and thalamic lesions (TLs) were expert-quantified. Wilcoxon rank-sum, two-sample t-tests and Spearman’s correlations were investigated.

Results

LME was found in 17/25 (68%) RRMS subjects at baseline and 18/25 (72%) at follow-up vs. a single stable focus in 1/12 HC (8.3%). In the RRMS group, 42 LME foci [mean 2.5±1.1 (range 1-5) per LME+ subject] were identified at baseline versus 48 foci [2.7±1.2 (1-5)] at follow-up. LME foci number at follow-up was unchanged in 18 (72%) RRMS subjects, increased in 6 (24%), decreased in 1 (4%). All 6 subjects with increased LME foci were on treatment [glatiramer acetate, interferon-β (2), rituximab, ocrelizumab, fingolimod]. The subject with LME resolution was treated with ocrelizumab. LME+ subjects had an on-study increase in volume of WMLs (baseline 11.0±14.4 vs. follow-up 12.6±16.3 ml, p<0.001), CLs (0.85±1.2 vs. 1.0±1.4 ml, p=0.002) and TLs (0.103±0.093 vs. 0.117±0.099 ml, p=0.005), whereas LME- subjects had an increase only in WML volume (2.7±2.3 vs. 3.3±2.6 ml, p=0.023). Baseline LME foci number correlated with 1-year change in CL (r=0.36, p=0.078) and WML (r=0.50, p=0.010) volumes. Minimal EDSS change over 1 year was noted. We used these data as the basis for a sample size calculation for a hypothetical trial of a putative therapy that would reduce the rate of MRI lesion accrual by 80% over 1 year. For a single-arm study with 1-year run-in on standard therapy and 1 year on new treatment to achieve 80% power, sample sizes of n=46, n=56 and n=79 were calculated for CL volume, TL volume and LME foci number, respectively.

Conclusions

The evolution of cerebral LME may be a dynamic process in the short term in RRMS, providing a monitoring tool, with about one quarter of patients showing new foci at one year. LME may pose a risk for the subsequent development of new lesions in widespread brain regions, implicating meningeal involvement as a marker or mediator of increased disease severity.

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Invited Presentations Invited Abstracts

PS03.01 - MRI Phenotypes and miRNA Signatures in MS

Speakers
Presentation Number
PS03.01
Presentation Topic
Invited Presentations
Lecture Time
10:30 - 10:45

Abstract

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.

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Author Of 6 Presentations

Biostatistical Methods Late Breaking Abstracts

LB1194 - Analysis of count data in MS clinical trials (ID 2013)

Speakers
Authors
Presentation Number
LB1194
Presentation Topic
Biostatistical Methods

Abstract

Background

Count outcomes are common in clinical studies of multiple sclerosis (MS), but the methods for the analysis of count outcomes are not commonly discussed in introductory statistics courses.

Objectives

To introduce commonly used statistical approaches for clinical studies of MS with a focus on the similarities and differences between the approaches.

Methods

For this session, data was simulated to mimic two recent MS clinical trials. The first dataset was simulated to mimic a phase III clinical trial with the number of relapses as the outcome. The second dataset was simulated to mimic a phase II clinical trial with the number of new gadolinium enhancing lesions on a brain MRI as the outcome.

Results

When the goal is to analyze the number of new relapses, a commonly used approach is Poisson regression. This approach estimates the rate ratio and easily accommodates different follow-up intervals for each subject by including an offset in the model. This approach is related to a comparison of incidence rates and the analysis of recurrent events using survival analysis. When the goal is to analyze the number of new lesions, Poisson regression is usually not appropriate because the mean and variance of the number of new lesions are often quite different due to a small number of subjects having a large number of new lesions. This leads to highly skewed data. To analyze this outcome, Poisson regression with robust standard errors or negative binomial regression are preferred because these approaches accommodate overdispersion. Results from the statistical software package Stata will be shown to demonstrate the commands described in the session.

Conclusions

Count outcomes are common in MS clinical studies, and specific analysis approaches are used for these outcomes. Many of the analysis approaches used for count outcomes are related, but each approach makes different assumptions so the best approach will depend on the outcome of the study.

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Prognostic Factors Poster Presentation

P0488 - Relapse recovery in MS: Effect of treatment and contribution to long-term disability (ID 1039)

Speakers
Presentation Number
P0488
Presentation Topic
Prognostic Factors

Abstract

Background

Although a small number of studies has shown that recovery from relapses in multiple sclerosis appears to contribute to long-term outcomes, relapse recovery has largely been ignored as a treatment endpoint and predictor of disability. We hypothesized that relapse recovery in the early stages of disease will impact longer term disability.

Objectives

The first aim of this study was to identify demographic and clinical predictors associated with incomplete recovery from relapses in the first 3 years from the first MS symptom. The second aim was to examine the relationship between incomplete recovery in first 3 years and 10-year disability outcomes.

Methods

Recovery from relapses in the first three years from the first symptom was retrospectively assessed in 360 patients with relapsing remitting multiple sclerosis enrolled in the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB study), a large longitudinal cohort. Complete or incomplete recovery from each relapse was determined based on the return of the Expanded Disability Status Scale (EDSS), Functional System Scale (FSS) and neurologic signs to baseline levels at least 6 months after symptom onset. Univariate and multivariable models were used to associate recovery with demographic and clinical factors and to predict 10-year disability and MRI outcomes (brain parenchymal fraction and T2 lesion volume).

Results

Including their initial episode, the 360 included patients had a total of 736 relapses within the first three years from their first symptom. 44.6% of these relapses had an incomplete recovery at 6 months. Relapses in untreated patients had an incomplete recovery in 51.8% of cases, compared to 28.9% in patients who were being treated with a disease modifying drug (p<0.001). In the multivariable analysis, recovery from relapses in the first 3 years was better younger patients, who were on interferon treatment, had no bowel or bladder symptoms and had a longer interval since their first symptom. For every incomplete recovery in the first three years, the EDSS at 10 years increased by 0.6 points, and the timed 25-foot walk at 10 years increased by 0.5 seconds. Both disability outcomes were also higher with older age at first symptom and higher BMI. Brain atrophy, measured by the brain parenchymal fraction on MRI, was associated only with older age at first symptom, whereas T2-hyperintense lesion volume was only associated with smoking.

Conclusions

Early initiation of first-line disease-modifying treatments can improve relapse recovery, which in turn prevents long-term disability.

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Observational Studies Poster Presentation

P0871 - Efficacy and safety of dimethyl fumarate in progressive multiple sclerosis (ID 1547)

Presentation Number
P0871
Presentation Topic
Observational Studies

Abstract

Background

Dimethyl fumarate (DMF) is an FDA approved drug for relapsing forms of multiple sclerosis. Currently, there is limited data analyzing the safety and efficacy of DMF in progressive multiple sclerosis (PMS) population. A combination of immunomodulatory and neuroprotective effects demonstrated with DMF could theoretically benefit this subset of patients.

Objectives

To analyze the safety and efficacy of dimethyl fumarate in patients diagnosed with progressive forms of multiple sclerosis.

Methods

We conducted a single-center retrospective observational analysis of patients with PMS assessing the safety and efficacy of DMF. We used Cox proportional hazards models to compare the time to sustained worsening and improvement on the Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) between patients treated with DMF and glatiramer acetate (GA) for at least one year. A multivariable analysis adjusting for age, sex, disease duration, and baseline EDSS was also performed.

Results

Eighty-eight patients were included in this study, 46 patients in the DMF group and 42 in the GA group. Safety and tolerability of GA and DMF were consistent with established profiles. There was a non-significant reduction in sustained EDSS and T25FW progression in the DMF group compared to the GA group after adjustment (HR=0.74; 95% CI: 0.32, 1.70; p=0.46 and HR=0.51; 95% CI: 0.21, 1.21; p=0.12, respectively). Sustained EDSS improvement showed a significant difference in the DMF group compared to the GA group (HR=4.23; 95% CI: 1.09, 16.42; p=0.04) after adjustment.

Conclusions

In a well-characterized PMS population, DMF showed a consistent though non-significant reduction of disease progression metrics and a significant increase in proportion of patients experiencing sustained EDSS improvement compared to patients treated with GA. The small sample precluded definitive determination though suggested that further study of DMF in PMS is warranted.

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Observational Studies Poster Presentation

P0918 - Teriflunomide safety and efficacy in advanced progressive multiple sclerosis (ID 1541)

Presentation Number
P0918
Presentation Topic
Observational Studies

Abstract

Background

Teriflunomide is an FDA approved medication for relapsing-remitting multiple sclerosis. The efficacy of teriflunomide in progressive multiple sclerosis is not well characterized.

Objectives

To explore the safety and efficacy profile of teriflunomide in patients diagnosed with progressive multiple sclerosis.

Methods

We conducted a single-center retrospective observational analysis of a progressive multiple sclerosis population, assessing safety and efficacy in patients treated at least one year with teriflunomide or glatiramer acetate. Sustained progression of expanded disability status scale (EDSS) and sustained worsening of timed 25-foot walk (T25FW) were compared using a cox proportional hazards model.

Results

Teriflunomide group (n=29) mean characteristics: age=58 years (SD±7.6), disease duration=16.7 years (SD±9.5), EDSS =5.9 (SD±1.3), follow-up=32.4 months (SD±13.6). Glatiramer acetate group (n=30) mean characteristics: age=52.4 years (SD±11.3), disease duration=15.1 years (SD±10.4), EDSS =5.7 (SD±1.6), follow-up=46.9 months (SD±43.9). Both treatments were well tolerated without serious side effects. After adjustment for age, sex, and baseline EDSS, sustained EDSS progression did not differ between groups (Hazard Ratio =1.17; 95% Confidence Interval: 0.45, 3.08; p=0.75). Sustained T25FW worsening after adjustment also did not differ (Hazard Ratio =0.56; 95% Confidence Interval: 0.2, 1.53; p=0.26).

Conclusions

In an advanced progressive multiple sclerosis population no substantial differences in tolerability, safety, sustained EDSS progression, or sustained T25FW worsening over time were observed between glatiramer acetate and teriflunomide treated groups.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1010 - Comparison of Models for Disability Accumulation on the Expanded Disability Status Scale in Multiple Sclerosis (ID 1665)

Speakers
Presentation Number
P1010
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

When assessing long-term trends in disability accumulation and economic models to compare treatments in multiple sclerosis (MS), disability accumulation on the Expanded Disability Status Scale (EDSS) is commonly assumed to depend only on the present state of the patient. Such models also often assume that the probability of disability accumulation is constant over the disease course.

Objectives

The objective of this study was to assess the assumptions of models used to describe disability accumulation within patients with MS.

Methods

Patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB) who had ≥6 consecutive clinic visits, which occurred every 6 months, were included in this analysis. This yielded 7257 observations for 1039 patients. To assess whether a previous EDSS score only was sufficient for modeling disability accumulation, we compared 2 models for EDSS transitions with the EDSS scale grouped into 3 score levels (0–1.5, 2–3.5, ≥4) using a likelihood ratio test. The first transition model included only the present EDSS score, and the second model included the present and the previous EDSS scores. In addition, we fit a repeated measures proportional odds model with 1, 2, and 3 previous EDSS scores to assess if additional previous EDSS scores added to the model. To determine if the probability of disability accumulation changed with time, we assessed whether disease duration <15 years or ≥15 years was associated with a change in the transition matrix using a likelihood ratio test. Finally, we fit the repeated measures proportional odds model to assess if disease duration improved the model that included 3 previous EDSS scores.

Results

When the model with only the present EDSS score was compared with the model with 2 previous EDSS scores, the model including the 2 previous EDSS scores led to a better model fit (P<0.001). Further, all previous EDSS scores were associated with subsequent EDSS score in the repeated measures proportional odds model (1 previous EDSS, OR [95% CI]: 4.64 [4.31–4.99]; 2 previous EDSS, OR [95% CI]: 1.77 [1.65–1.90]; 3 previous EDSS, OR [95% CI]: 1.63 [1.53–1.73]). Incorporating disease duration also improved model fit using both approaches (P<0.001 for each method).

Conclusions

Additional EDSS history and disease duration may be important to incorporate into disability accumulation modeling for MS.

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Invited Presentations Invited Abstracts

TC14.02 - Presentation 02 (ID 630)

Speakers
Authors
Presentation Number
TC14.02
Presentation Topic
Invited Presentations

Presenter Of 3 Presentations

Biostatistical Methods Late Breaking Abstracts

LB1194 - Analysis of count data in MS clinical trials (ID 2013)

Speakers
Authors
Presentation Number
LB1194
Presentation Topic
Biostatistical Methods

Abstract

Background

Count outcomes are common in clinical studies of multiple sclerosis (MS), but the methods for the analysis of count outcomes are not commonly discussed in introductory statistics courses.

Objectives

To introduce commonly used statistical approaches for clinical studies of MS with a focus on the similarities and differences between the approaches.

Methods

For this session, data was simulated to mimic two recent MS clinical trials. The first dataset was simulated to mimic a phase III clinical trial with the number of relapses as the outcome. The second dataset was simulated to mimic a phase II clinical trial with the number of new gadolinium enhancing lesions on a brain MRI as the outcome.

Results

When the goal is to analyze the number of new relapses, a commonly used approach is Poisson regression. This approach estimates the rate ratio and easily accommodates different follow-up intervals for each subject by including an offset in the model. This approach is related to a comparison of incidence rates and the analysis of recurrent events using survival analysis. When the goal is to analyze the number of new lesions, Poisson regression is usually not appropriate because the mean and variance of the number of new lesions are often quite different due to a small number of subjects having a large number of new lesions. This leads to highly skewed data. To analyze this outcome, Poisson regression with robust standard errors or negative binomial regression are preferred because these approaches accommodate overdispersion. Results from the statistical software package Stata will be shown to demonstrate the commands described in the session.

Conclusions

Count outcomes are common in MS clinical studies, and specific analysis approaches are used for these outcomes. Many of the analysis approaches used for count outcomes are related, but each approach makes different assumptions so the best approach will depend on the outcome of the study.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1010 - Comparison of Models for Disability Accumulation on the Expanded Disability Status Scale in Multiple Sclerosis (ID 1665)

Speakers
Presentation Number
P1010
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

When assessing long-term trends in disability accumulation and economic models to compare treatments in multiple sclerosis (MS), disability accumulation on the Expanded Disability Status Scale (EDSS) is commonly assumed to depend only on the present state of the patient. Such models also often assume that the probability of disability accumulation is constant over the disease course.

Objectives

The objective of this study was to assess the assumptions of models used to describe disability accumulation within patients with MS.

Methods

Patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB) who had ≥6 consecutive clinic visits, which occurred every 6 months, were included in this analysis. This yielded 7257 observations for 1039 patients. To assess whether a previous EDSS score only was sufficient for modeling disability accumulation, we compared 2 models for EDSS transitions with the EDSS scale grouped into 3 score levels (0–1.5, 2–3.5, ≥4) using a likelihood ratio test. The first transition model included only the present EDSS score, and the second model included the present and the previous EDSS scores. In addition, we fit a repeated measures proportional odds model with 1, 2, and 3 previous EDSS scores to assess if additional previous EDSS scores added to the model. To determine if the probability of disability accumulation changed with time, we assessed whether disease duration <15 years or ≥15 years was associated with a change in the transition matrix using a likelihood ratio test. Finally, we fit the repeated measures proportional odds model to assess if disease duration improved the model that included 3 previous EDSS scores.

Results

When the model with only the present EDSS score was compared with the model with 2 previous EDSS scores, the model including the 2 previous EDSS scores led to a better model fit (P<0.001). Further, all previous EDSS scores were associated with subsequent EDSS score in the repeated measures proportional odds model (1 previous EDSS, OR [95% CI]: 4.64 [4.31–4.99]; 2 previous EDSS, OR [95% CI]: 1.77 [1.65–1.90]; 3 previous EDSS, OR [95% CI]: 1.63 [1.53–1.73]). Incorporating disease duration also improved model fit using both approaches (P<0.001 for each method).

Conclusions

Additional EDSS history and disease duration may be important to incorporate into disability accumulation modeling for MS.

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Invited Presentations Invited Abstracts

TC14.02 - Presentation 02 (ID 630)

Speakers
Authors
Presentation Number
TC14.02
Presentation Topic
Invited Presentations

Moderator Of 1 Session

Teaching Course Fri, Sep 11, 2020
Session Type
Teaching Course
Date
Fri, Sep 11, 2020

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

TC14.02 - Presentation 02 (ID 630)

Speakers
Authors
Presentation Number
TC14.02
Presentation Topic
Invited Presentations