Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Patient-reported financial toxicity in multiple sclerosis: Predictors and association with care non-adherence.

BACKGROUND: Multiple sclerosis (MS) results in considerable financial burdens due to expensive treatment and high rates of disability, which could both impact care non-adherence. OBJECTIVE: To measure financial toxicity in MS patients, identify its predictors and association with care non-adherence. METHODS: Adult MS patients visiting neurology clinic (June 2018 to February 2019) were consented to complete a survey. Financial toxicity was measured using Comprehensive Score for Financial Toxicity (COST) (range: 0-44, the lower the score, the worse the financial toxicity). Independent predictors of financial toxicity were identified using linear regression. Associations of COST score with patient outcomes were assessed. RESULTS: The mean COST score in 243 recruited patients was 17.4 ± 10.2. In response to financial burdens, 66.7% and 34.7% reported life-style altering behaviors or care non-adherence, respectively. Higher financial self-efficacy was associated with less financial toxicity (coefficient, 1.33 (95% confidence interval (CI), 1.02-1.64); p < 0.001). At least one relapse in the last 3 months was associated with greater financial toxicity (coefficient, -3.34 (95% CI, -6.66 to -0.01); p = 0.049). Greater financial toxicity correlated with life-style-altering coping strategy use (p < 0.001), care non-adherence (p = 0.001), and worse health-related quality of life (HRQOL) (p = 0.03). CONCLUSION: MS patients with lower financial self-efficacy and prior relapse history are at higher risk for financial toxicity, with associated care non-adherence and lower HRQOL.

Factors associated with benign multiple sclerosis in the New York State MS Consortium (NYSMSC).

BACKGROUND: This retrospective analysis explored prognostic factors associated with a benign multiple sclerosis (BMS) disease course at baseline and over the 4-year follow-up. METHODS: Patients from the centralized New York State Multiple Sclerosis Consortium registry were classified as having BMS according to 3 different criteria centered on disease duration and disability. Additional analyses explored prognostic factors associated with BMS using the most conservative disability criteria (Expanded Disability Status Scale ≤2 and disease duration ≥10 years). RESULTS: Among 6258 patients who fulfilled eligibility criteria, 19.8 % to 33.3 % were characterized as having BMS, at baseline depending on classification criteria used. Positive prognostic factors for BMS at baseline included female sex (p < 0.0001) and younger age at onset (p < 0.0001); negative prognostic factors included progressive-onset type of MS and African-American race. Of the 1237 BMS patients (per most conservative criteria), 742 were followed for a median of 4 years to explore effect of disease-modifying treatment (DMT) on benign status. DMT (p = 0.009) and longer disease duration (p = 0.007) were the only significant positive predictors of maintaining BMS at follow-up. The protective effect was stronger for patients taking DMT at both enrollment and follow-up (OR = 0.71; p = 0.006). CONCLUSIONS: There is a need for development of more reliable prognostic indicators of BMS. Use of DMT was significantly associated with maintaining a benign disease state.

Patient-Specific Out-of-Pocket Cost Communication and Remote Financial Navigation in Patients with Multiple Sclerosis: A Randomized Controlled Feasibility Study.

OBJECTIVE: We conducted a randomized controlled trial evaluating the feasibility of a personalized out-of-pocket cost communication, remote financial navigation and counseling (CostCOM) intervention in decreasing financial hardship among patients with multiple sclerosis (MS). METHODS: Sixty-two adult patients with diagnosis of MS and a prescription for a disease modifying therapy were randomized into: (1) Usual care (n=30) and (2) CostCOM (n=32). CostCOM included patient-specific out-of-pocket cost communication, remote financial navigation and counseling delivered at enrollment and 3 months. Usual care included routine neurology visits, use of available ancillary staff, and internal or external resources for financial assistance per normal clinic procedures. Feasibility outcomes included participation in and satisfaction with CostCOM. Exploratory financial hardship outcomes included cost-related care nonadherence, material hardship, and financial worry using Comprehensive Score for Financial Toxicity (COST). RESULTS: Mean age was 41.5 (81.0% female; 41.4% White and 51.7% Black race). Of 32 CostCOM patients, 96.8% and 68.7% completed baseline and follow-up intervention. A financial assistance application was completed for 80%. Mean general satisfaction (out of 5) with CostCOM was 3.1±1.0. In multivariable analyses, CostCOM patients had less financial worry (i.e., higher COST scores) at 3 months compared to usual care patients (B coefficient, 3.6; 95% CI (0.1 - 7.1). While CostCOM patients had significant decreases in 3 months non-adherence (72.7%) compared to enrollment (50%), their 3 months nonadherence and material hardship were not significantly different between the two arms. CONCLUSION: CostCOM interventions are feasible, acceptable, and yield potential benefits in decreasing financial hardship. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT04257071).

Longitudinal changes of financial hardship in patients with multiple sclerosis.

OBJECTIVE: To measure the longitudinal changes in three domains of financial hardship (i.e., financial worry, cost-related care non-adherence, material hardship) in patients with MS. METHODS: A convenience sample of 559 adult patients with a known diagnosis of MS visiting a single outpatient neurology clinic between July 2018 to February 2020 were approached. Patients completed surveys at baseline and 3, 6, 9, and 12 months post-enrollment. Outcomes included financial worry (using Comprehensive Score for Financial Toxicity Patient-Reported Outcome (COST)), cumulative cost-related care non-adherence, and cumulative financial hardship as adopted by Medical Expenditure Panel Survey (MEPS). Associations of financial worry with care non-adherence and material hardship were assessed using ANOVA. RESULTS: A total of 242 (43.3%) participated at baseline. Mean age was 43.6 ± 13.6 years (76.9% female; 46.4% White); median months from diagnosis was 63 (IQR, 28-120). The mean COST score at enrollment was 17.43 (± 10.15) and increased to 19.41 (± 11.12) at 12 months (p = 0.09). Cumulative cost-related MS care non-adherence increased from 32.6% at baseline to 53.3% at 12 months (20.7% increase; p <0.001). Cumulative material hardship increased from 61.6% at baseline to 76.0% at 12 months (14.4% increase; p<0.001). Changes in COST score from baseline to 12 months were significantly associated with changes in non-adherence and material hardship (p<0.01). CONCLUSION AND RELEVANCE: Cost-related care non-adherence and material hardship accumulate progressively over time and correlates with financial worry. Clinical practices should focus on screening those at risk and intervene with the goal of mitigating costs of care and improving patient outcomes.

Neuromyelitis Optica Presenting as Infectious Meningoencephalitis: Case Report and Literature Review.

In this patient-focused review, we present a 34-year-old previously healthy man admitted for fever and headache two weeks after a motor vehicle accident. On admission, his workup was concerning for meningoencephalitis based on elevated cerebrospinal fluid (CSF) white blood cell count and elevated CSF protein. He was admitted for management of meningoencephalitis. During his course, no causative infectious agent was identified despite an extensive workup. He additionally underwent an autoimmune and paraneoplastic workup that was negative. During his hospitalization, he developed acute transverse myelitis manifested by bilateral lower extremity paralysis. After four weeks marked by persistent clinical deterioration, brain biopsy was performed. Pathologic examination was consistent with neuromyelitis optica spectrum disorder (NMOSD). In this case report and literature review, we explore the presentations of NMOSD that mimic an infection. Clinicians should be aware of the possibility of NMOSD masquerading as infectious meningoencephalitis or acute transverse myelitis.

Perceptions and experiences of multiple sclerosis patients regarding out-of-pocket costs of care discussions.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a costly disease and out-of-pocket (OOP) cost information is difficult to obtain. We seek to characterize the perceptions and experiences of MS patients regarding out-of-pocket (OOP) costs of care discussions and evaluate factors associated with them. MATERIALS AND METHODS: MS patients visiting an outpatient neurology clinic 7/2018-2/2019 were approached to complete a survey regarding costs of care discussions. Logistic regression analyses were performed to identify factors associated with patient preferences in discussing OOP costs with their provider and actions to contact insurance company to inquire about OOP costs. RESULTS: A total of 243 patients responded (response rate 43.5%). With regard to perceptions, 85.3% of patients expressed interest in knowing about OOP costs, 59.6% reported desire specifically for their healthcare provider to discuss OOP costs, and 18.5% reported that there have been times they wanted to discuss OOP costs but did not have the opportunity to do so. With regard to experiences, 20.5% reported discussing costs with their providers in the past three months, 15.5% contacted their insurance company regarding OOP costs, and 10.6% received a call from an imaging center to inform them of OOP costs. Patients who were male, white, or had at least one relapse were significantly more likely to desire to discuss OOP costs with their provider. No factors were significantly associated with patients contacting their insurance company regarding OOP costs. CONCLUSION: Most MS patients would like to discuss costs of care with their providers, but only one in five actually do so. Medical practices can take initiatives towards providing transparency in OOP costs.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Blood B Cell and Regulatory Subset Content in Multiple Sclerosis Patients.

OBJECTIVE: B cell targeted therapies have been effective in slowing multiple sclerosis (MS) disease progression suggesting a direct causal link for this lymphoid subset. A small subset of B cells with regulative properties (Bregs) exists in peripheral blood, and induction of Bregs ameliorates experimental autoimmune encephalomyelitis (EAE), the murine model for MS. Therefore the frequency of B cell subsets and regulatory B cells in particular in peripheral blood of MS patients is of interest. METHODS: The phenotype and frequency of B cell subsets in peripheral blood from 32 MS patients and 34 healthy controls (HC) were examined using flow cytometry. RESULTS: We found that there is an increase in CD19+ cell number in MS 1347 ± 159 cells/µL, (average ± SEM) compared to HC, 935 ± 129 cells/µL and no apparent deficiency in B-cells with a regulatory phenotype. In addition, we observed a loss of correlation between CD19+ B cells and total lymphocyte count in MS. CONCLUSION: These findings suggest altered blood B-cell homeostasis in MS patients.