Background

Despite an array of disease modifying therapies (DMTs), interferons/glatiramer acetate (IFN/GA) and dimethyl fumarate (DMF) are still the most frequently used to treat multiple sclerosis (MS) in United States.

Objectives

Our objective was to evaluate treatment patterns and disease breakthrough for patients initiating IFN/GA/DMF as first-line therapies to determine if there is an unmet need for more effective agents to be used first-line.

Methods

Adult MS patients (age ≥18) with ≥1 DMT claims of IFN/GA/DMF from January 2016-March 2018 were identified using a large US administrative claims database (IBM® MarketScan® Database). The date of the first MS DMT claim was defined as the index date and patients were followed for one year. Treatment switch was defined as changing from initial therapy to another DMT (within 60 days) and discontinuation was defined as no DMT use for at least 60 days after stopping the initial DMT. Breakthrough-disease was defined as occurrence of relapse (characterized via a validated claims algorithm) during the treatment period. Outcomes were evaluated as a combined DMT group and by individual DMTs.

Results

We identified 1,096 patients initiating IFN/GA and 565 patients initiating DMF. Of these, 43.4% experienced treatment failure (29.3% discontinued or 14.1% switched DMTs) within one year of initiation (results for individual DMTs were similar). The median time to discontinuation was 4.8 months, and the median time to switch was 5.6 months. Approximately, 28.2% of patients experienced at least 1 relapse over the 1-year observation period. The median time to relapse was 4.6 months. There was no reduction in annualized relapse rate (ARR) after initiation of IFN/GA/DMF therapy [ARR for 1-year prior to initiation = (0.41) and 1 year post-initiation = (0.42)].

Conclusions

There is an unmet need for early use of high efficacy DMT, as the most frequently used first-line DMTs show treatment failure (discontinuation/switching/disease-breakthrough) and lack of treatment benefit at high rates in a real-world setting.

Background

The impact of comorbidities on multiple sclerosis (MS) disease course has been a recent focus of research. Hypertension, in particular, has been associated with worsened clinical outcomes and low quality of life in patients with MS. Thus, the adequate control of blood pressure is an important aspect of the overall care provided to MS patients. We investigated whether MS patients who have evidence of hypertension are being appropriately treated with anti-hypertensive medications.

Objectives

To determine whether MS patients with evidence of hypertension are being treated with anti-hypertensive medications.

Methods

We used the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS, funded by Biogen) international database and identified MS patients with in-office evidence of hypertension (American Heart Association 2017 Guidelines definition: systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg). We assessed whether these patients were receiving anti-hypertensive medications.

Results

A total of 10,635 patients were identified with mean age 48.2 years (SD=12.6) and mean disease duration 12 years (SD=9.6). The mean number of blood pressure (BP) measurements per patient was 2.4 (SD=1.9). There were 9,760 (91.8%) patients with BP measurements. Of those, 2,718 (27.9%) had at least two BP measurements with systolic BP (SBP) ≥130 mm Hg and/or diastolic BP (DBP) ≥80 mm Hg. In patients with two elevated BP readings, 997 (36.7%) were receiving treatment with anti-hypertensive medication. Of all patients with BP measurements, 1,019 (10.4%) had at least two BP measurements with SBP ≥140 mm Hg and/or DPB ≥90 mm Hg. Of these, 474 (46.2%) were receiving anti-hypertensive medications. Angiotensin converting enzyme inhibitors, beta-blockers and diuretics were the most commonly used anti-hypertensive medications.

Conclusions

Hypertension appears to be undertreated in patients with MS and its management deserves attention from MS specialists.

Background

Hypertension (HTN) is a common condition in multiple sclerosis (MS), and it is associated with poorer MS outcomes. Recently, a large study showed HTN was 25% more common in MS than non-MS cohorts. It is unknown if the elevated HTN prevalence is because vascular alterations play a primary role in MS pathogenesis or if they are secondary to MS disease processes.

Objectives

To add insight to the MS-HTN relationship, we sought to determine if HTN age at onset (AAO) is earlier in MS patients compared to matched controls.

Methods

Using electronic health records (EHRs) from the Cleveland Clinic Health System (CCF), we identified 141,696 incident HTN diagnoses among Ohio residents between 1/2000-1/2017 who were ≥18 years at 1^st encounter. Incident HTN was defined as the 1^st of ≥2 recorded HTN diagnoses at least 3 months after the 1^st encounter. Similar criteria determined incident MS (N=546). We then matched MS cases to controls on birth year (+/- 3 years), age at 1^st encounter (+/- 3 years), sex, race and ZIP code, allowing for up to 10 matches. By matching in this retrospective cohort, where MS status is the exposure of interest, we remove potential confounding in the observed relationship of interest due to the matched variables. The final data set consisted of 509 MS cases and 4,522 matched controls; 87% MS cases were matched to ≥7 controls. Using HTN AAO as the dependent variable, we conducted Cox Proportional Hazards (CPH) and linear regression (LR) models with standard errors adjusted for intragroup correlations due to matching. Based on quartiles of the distribution of birth year in MS cases (1920-1949, 1950-1957, 1958-1965, 1966-1990), we constructed a categorical variable to be included as a covariate along with age at 1^st encounter, sex, race, and smoking status (ever/never).

Results

Birth year violated the PH assumption, therefore stratified CPH models across birth year categories were conducted. MS and age at 1^st encounter were time-varying, and treated as such. On average MS cases had a 73% increased hazards (HR = 1.73, 95% CI: 1.17, 2.55; p=0.006) for HTN onset, which decreased by 1% per year increase in age. Since the effect of MS was time-varying, we conducted models per birth year category. Interesting, MS was not associated with increased hazards for HTN onset for those born before 1966. In those born after 1965, MS was associated with a 37% increased hazards (HR = 1.37, 95% CI: 1.12, 1.68; p=0.0025), and this effect met the PH assumption.

From the LR model, there was an interaction between MS and birth year, therefore similar stratifed models were conducted. HTN AAO was on average 0.7 years earlier (95% CI: 0.05, 1.4; p=0.04) in MS cases than controls born after 1965. There were no difference for other birth year categories.

Conclusions

In those born after 1965, persons with MS experience an earlier onset of HTN. Future research is needed to characterize these relatioships by sex and race, as well as the timing of HTN onset with respect to MS onset.

Background

Vascular comorbidities like diabetes, hypertension and dyslipidemia are overrepresented in people with multiple sclerosis (MS) and may contribute to adverse MS outcomes. Existing studies evaluating vascular comorbidity and MS course were often limited by relatively small sample sizes or lack large-scale corresponding quantitative neuroimaging studies.

Objectives

To assess the association between vascular comorbidity burden with clinical and imaging features of disease severity in a large population of people with MS.

Methods

We included participants from the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort. We evaluated if metabolic and vascular comorbidities (diabetes, hypertension and dyslipidemia) or a composite sum of vascular comorbidities was associated with MS characteristics, including objective neurologic function assessments and quantitative brain MRI measurements, after adjusting for covariates using propensity score weighted models.

Results

11,506 participants (6409 [55%] with brain MRI) were included in the analysis. Participants were on average aged 48.9 years (standard deviation [SD]: 12.4 years), were 74% female, and were 24% non-white; 1881 (16.3%) individuals had 2+ comorbidities. Individuals with 2+ vascular comorbidities had slower walking speed (-0.49 SD times slower; 95% CI: -0.78 to -0.19; p=0.001), slower manual dexterity (-0.41 SD times slower; 95% CI: -0.57 to -0.26; p<0.0001), and fewer correct scores on cognitive processing speed (-0.11 SD lower scores; -0.20 to -0.02; p=0.03) relative to those with none of these comorbidities. Those with 2+ had lower brain parenchymal (-0.41%, 95% CI -0.64%, -0.17%; p=-0.0001) and gray matter fractions (-0.30%, 95% CI -0.49, -0.10; p=0.002), including reduced cortical (-10.10 mL, 95% CI -15.42, -4.78; p=0.0002) and deep (-0.44 mL, 95% CI -0.84, -0.04; p=0.03) gray matter volumes, when compared to those with no comorbidity. Comorbidity burden was not associated with T2 lesion volume. Individually, diabetes and dyslipidemia were generally associated with poorer neuroperformance and brain imaging outcomes.

Conclusions

Increased vascular comorbidity burden was associated with clinical and imaging markers of MS severity in this large study. Strategies to optimize comorbidity management in people with MS are warranted.

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and can impair processing speed, episodic memory, and executive function. Magnetic resonance imaging (MRI) studies have demonstrated associations between several MRI metrics and cognitive functioning in MS, including thalamic volume and brain parenchymal fraction. Fingolimod is an MS therapy that demonstrated reduced brain volume loss across several clinical trials.

Objectives

Determine the relationship between cognitive function in fingolimod-treated relapsing-remitting MS patients and 7 tesla (7T) MRI measures.

Methods

We recruited fingolimod-treated MS patients and healthy controls to be followed for 12 months. Participants underwent 7T brain MRI and cognitive testing including the symbol digit modalities test (SDMT), selective reminding test (SRT), and the trail making, color, and verbal subtests of the Delis-Kaplan Executive Function System (DKEFS) at baseline, 6 months, and 12 months. Mixed effects linear regression models were used to determine the relationship between MRI metrics and neurometric test performance, fitting values from all 3 time points. Rates of change in MRI metrics and neurometric test performance were compared between patients and controls using two-sample t-tests.

Results

We enrolled 15 MS patients with mean age 42.4 years (SD=5.6), mean disease duration 8.5 years (SD=4.1), and median expanded disability status scale 3 (IQR=1.5-3.5). Five controls were enrolled with mean age 41.5 (SD=6.6) years. Controls performed better than patients on all psychometric tests, but this was only significant for tests of orthographic knowledge (DKEFS letter fluency) and long-term storage (SRT). When MRI metrics were used to predict neuropsychological test performance over time in patients, thalamic volume was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and inhibitory control (DKEFS Color Inhibition). Thalamic myelin density was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and semantic knowledge (DKEFS Verbal Category Fluency). When changes in neuropsychological testing performance and MRI metrics were compared for patients and controls from 0-6 months, and from 0-12 months, none of the differences between patients and controls were significant.

Conclusions

Thalamic volume and myelin density are associated with measures of cognitive function. 7T MRI of the thalamus may be useful as a clinical trial measure to predict cognitive effects.

Background

Despite an array of disease modifying therapies (DMTs), interferons/glatiramer acetate (IFN/GA) and dimethyl fumarate (DMF) are still the most frequently used to treat multiple sclerosis (MS) in United States.

Objectives

Our objective was to evaluate treatment patterns and disease breakthrough for patients initiating IFN/GA/DMF as first-line therapies to determine if there is an unmet need for more effective agents to be used first-line.

Methods

Adult MS patients (age ≥18) with ≥1 DMT claims of IFN/GA/DMF from January 2016-March 2018 were identified using a large US administrative claims database (IBM® MarketScan® Database). The date of the first MS DMT claim was defined as the index date and patients were followed for one year. Treatment switch was defined as changing from initial therapy to another DMT (within 60 days) and discontinuation was defined as no DMT use for at least 60 days after stopping the initial DMT. Breakthrough-disease was defined as occurrence of relapse (characterized via a validated claims algorithm) during the treatment period. Outcomes were evaluated as a combined DMT group and by individual DMTs.

Results

We identified 1,096 patients initiating IFN/GA and 565 patients initiating DMF. Of these, 43.4% experienced treatment failure (29.3% discontinued or 14.1% switched DMTs) within one year of initiation (results for individual DMTs were similar). The median time to discontinuation was 4.8 months, and the median time to switch was 5.6 months. Approximately, 28.2% of patients experienced at least 1 relapse over the 1-year observation period. The median time to relapse was 4.6 months. There was no reduction in annualized relapse rate (ARR) after initiation of IFN/GA/DMF therapy [ARR for 1-year prior to initiation = (0.41) and 1 year post-initiation = (0.42)].

Conclusions

There is an unmet need for early use of high efficacy DMT, as the most frequently used first-line DMTs show treatment failure (discontinuation/switching/disease-breakthrough) and lack of treatment benefit at high rates in a real-world setting.

Background

The impact of comorbidities on multiple sclerosis (MS) disease course has been a recent focus of research. Hypertension, in particular, has been associated with worsened clinical outcomes and low quality of life in patients with MS. Thus, the adequate control of blood pressure is an important aspect of the overall care provided to MS patients. We investigated whether MS patients who have evidence of hypertension are being appropriately treated with anti-hypertensive medications.

Objectives

To determine whether MS patients with evidence of hypertension are being treated with anti-hypertensive medications.

Methods

We used the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS, funded by Biogen) international database and identified MS patients with in-office evidence of hypertension (American Heart Association 2017 Guidelines definition: systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg). We assessed whether these patients were receiving anti-hypertensive medications.

Results

A total of 10,635 patients were identified with mean age 48.2 years (SD=12.6) and mean disease duration 12 years (SD=9.6). The mean number of blood pressure (BP) measurements per patient was 2.4 (SD=1.9). There were 9,760 (91.8%) patients with BP measurements. Of those, 2,718 (27.9%) had at least two BP measurements with systolic BP (SBP) ≥130 mm Hg and/or diastolic BP (DBP) ≥80 mm Hg. In patients with two elevated BP readings, 997 (36.7%) were receiving treatment with anti-hypertensive medication. Of all patients with BP measurements, 1,019 (10.4%) had at least two BP measurements with SBP ≥140 mm Hg and/or DPB ≥90 mm Hg. Of these, 474 (46.2%) were receiving anti-hypertensive medications. Angiotensin converting enzyme inhibitors, beta-blockers and diuretics were the most commonly used anti-hypertensive medications.

Conclusions

Hypertension appears to be undertreated in patients with MS and its management deserves attention from MS specialists.

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and can impair processing speed, episodic memory, and executive function. Magnetic resonance imaging (MRI) studies have demonstrated associations between several MRI metrics and cognitive functioning in MS, including thalamic volume and brain parenchymal fraction. Fingolimod is an MS therapy that demonstrated reduced brain volume loss across several clinical trials.

Objectives

Determine the relationship between cognitive function in fingolimod-treated relapsing-remitting MS patients and 7 tesla (7T) MRI measures.

Methods

We recruited fingolimod-treated MS patients and healthy controls to be followed for 12 months. Participants underwent 7T brain MRI and cognitive testing including the symbol digit modalities test (SDMT), selective reminding test (SRT), and the trail making, color, and verbal subtests of the Delis-Kaplan Executive Function System (DKEFS) at baseline, 6 months, and 12 months. Mixed effects linear regression models were used to determine the relationship between MRI metrics and neurometric test performance, fitting values from all 3 time points. Rates of change in MRI metrics and neurometric test performance were compared between patients and controls using two-sample t-tests.

Results

We enrolled 15 MS patients with mean age 42.4 years (SD=5.6), mean disease duration 8.5 years (SD=4.1), and median expanded disability status scale 3 (IQR=1.5-3.5). Five controls were enrolled with mean age 41.5 (SD=6.6) years. Controls performed better than patients on all psychometric tests, but this was only significant for tests of orthographic knowledge (DKEFS letter fluency) and long-term storage (SRT). When MRI metrics were used to predict neuropsychological test performance over time in patients, thalamic volume was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and inhibitory control (DKEFS Color Inhibition). Thalamic myelin density was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and semantic knowledge (DKEFS Verbal Category Fluency). When changes in neuropsychological testing performance and MRI metrics were compared for patients and controls from 0-6 months, and from 0-12 months, none of the differences between patients and controls were significant.

Conclusions

Thalamic volume and myelin density are associated with measures of cognitive function. 7T MRI of the thalamus may be useful as a clinical trial measure to predict cognitive effects.