Review of Phase III Clinical Trials Outcomes in Patients with Secondary Progressive Multiple Sclerosis.

OBJECTIVE: Few satisfyingly effective treatments exist for patients with Secondary Progressive Multiple Sclerosis (SPMS). Our goal in conducting this review is to highlight clinical outcomes and study design, which may be applied to future phase III clinical trials for patients with SPMS. METHODS: A review of the available literature of phase III clinical trials since 1990 that specifically studied patients with SPMS. PubMed and ClinicalTrials.org were searched using appropriate terms. RESULTS: Expanded Disability Status Scale (EDSS) was most often used as an outcome measure, with time to confirmed disability progression at three months being used most often. Components of the Multiple Sclerosis Functional Composite (MSFC) were the next most frequent primary outcome measure used. Patient Reported Outcomes (PROs) were frequently used as secondary outcome measures with specific PROs more successful than others. MRI measures related to brain parenchymal volume have recently started to be used in phase III clinical trials. CONCLUSIONS: Some successful trials may have been related to patient selection for less inflammatory disease, which confounds the comparison between successful trials. Time to confirmed disability at three months or changes in composite MSFC are reasonable primary outcome measures to use in future SPMS trials with a suggestion that the MSFC may be more sensitive to progressive disease changes. PROs and MRI measures following brain parenchymal volume are reasonable secondary outcome measures to incorporate into future phase III trials in SPMS.

Effectiveness and safety of dimethyl fumarate in progressive multiple sclerosis.

BACKGROUND: There is limited data analyzing the safety and effectiveness of dimethyl fumarate (DMF) in the progressive multiple sclerosis (PMS) population. OBJECTIVE: To analyze the safety and effectiveness of DMF in patients with PMS. METHODS: We used Cox proportional hazards models to compare the time to confirmed 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. RESULTS: We included 46 patients treated with DMF and 42 patients treated with GA. The safety and tolerability of GA and DMF were consistent with established profiles. There was no difference in confirmed EDSS progression. A trend towards reduced T25FW was seen in the DMF compared to GA after adjustment (HR = 0.86; 95% CI:0.37, 1.98; p = 0.72 and HR = 0.60; 95% CI:0.27, 1.34; p = 0.21, respectively). CONCLUSION: Dimethyl fumarate showed a trend towards reduction in T25FW but no evidence of clinically significant impact on EDSS. The small sample precluded definitive determination.

A possible case of serum sickness after ocrelizumab infusion.

A 41-year-old female diagnosed with multiple sclerosis began ocrelizumab treatment. She received her first treatment course without significant complication. After receiving the first maintenance dose 6 months later, she developed weakness, myalgias, gastrointestinal symptoms, headache, and intermittent fever persisting for 4 weeks. A working diagnosis of serum sickness was determined after excluding other probable entities. She received 3 days of 1 g methylprednisolone intravenously and five plasma exchanges, experiencing gradual improvement. Serum sickness has occurred with monoclonal antibodies including rituximab. This case of possible ocrelizumab-associated serum sickness suggests that clinicians should remain vigilant about this possibility with this medication.

Teriflunomide Safety and Efficacy in Advanced Progressive Multiple Sclerosis.

OBJECTIVES: To explore the safety and efficacy profile of teriflunomide in 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 and sustained worsening of timed 25-foot walk 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), expanded disability status score = 5.9 (SD ± 1.3), and 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), expanded disability status score = 5.7 (SD ± 1.6), and follow - up = 46.9 months (SD ± 43.9). Both treatments were well tolerated without serious side effects. After adjustment for age, sex, and baseline expanded disability status score, sustained expanded disability status score progression did not differ between groups (hazard ratio = 1.17; 95% confidence interval: 0.45, 3.08; p = 0.75). Sustained timed 25-foot walk worsening after adjustment also did not differ (hazard ratio = 0.56; 95% confidence interval: 0.2, 1.53; p = 0.26). CONCLUSION: 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. The small sample precluded definitive determination.

COVID-19 in teriflunomide-treated patients with multiple sclerosis.

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection. The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS. These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

An argument for broad use of high efficacy treatments in early multiple sclerosis.

Two different treatment paradigms are most often used in multiple sclerosis (MS). An escalation or induction approach is considered when treating a patient early in the disease course. An escalator prioritizes safety, whereas an inducer would favor efficacy. Our understanding of MS pathophysiology has evolved with novel in vivo and in vitro observations. The treatment landscape has also shifted significantly with the approval of over 10 new medications over the past decade alone. Here, we re-examine the treatment approach in light of these recent developments. We believe that recent work suggests that early prediction of the disease course is fraught, the amount of damage to the brain that MS causes is underappreciated, and its impact on patient function oftentimes is underestimated. These concerns, coupled with the recent availability of agents that allow a better therapeutic effect without compromising safety, lead us to believe that initiating higher efficacy treatments early is the best way to achieve the best possible long-term outcomes for people with MS.

Efficacy and safety of mycophenolate mofetil in progressive multiple sclerosis patients.

OBJECTIVES: There are increasingly effective therapies for relapsing forms of multiple sclerosis (MS); however, the options for the progressive patient population are limited. The effect of mycophenolate mofetil (MMF), a disease-modifying agent for several autoimmune diseases, in progressive MS has not been explored effectively. We performed a prospective study to assess the safety and efficacy of MMF in progressive MS patients. METHODS: We identified 64 patients enrolled in the comprehensive longitudinal database at the Partners MS Center, who fulfilled our inclusion criteria. They were exposed to MMF for at least 1 year with recorded clinical outcomes. Efficacy was assessed by comparing the absolute relapse rate (ARR), and the mean Expanded Disability Status Scale (EDSS) and timed 25 foot walk (T25FW) test scores before and after MMF treatment. RESULTS: At the start of MMF, 78% of patients (n = 50) were in the 4-7.5 EDSS range. There was a slight increase in mean EDSS from 5.49 ± 1.65 (n = 48) 1 year before MMF start to 5.85 ± 1.56 (n = 48) 1 year after (p = 0.020). The mean T25FW score increased 1 year before MMF from 12.3 ± 9.6 s (n = 38) to 15.6 ± 12.3 s (n = 38) 1 year after (p = 0.009). The ARR in the 2 years pre-MMF period was 0.30 ± 0.63, which decreased to a 0.09 ± 0.29 (p = 0.022) 2 years post MMF. CONCLUSION: MMF did not affect disease progression but did influence relapse rate. We believe that other medication options should be considered before MMF in advanced progressive patients.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.

OBJECTIVE: The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. DESIGN/METHODS: Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. RESULTS: We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml (-1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. CONCLUSIONS: DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.

A longitudinal uncontrolled study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis.

OBJECTIVE: Brain atrophy in multiple sclerosis (MS) selectively affects gray matter (GM), which is highly relevant to disability and cognitive impairment. We assessed cerebral GM volume (GMV) during one year of natalizumab therapy. DESIGN/METHODS: Patients with relapsing-remitting (n = 18) or progressive (n = 2) MS had MRI ∼1 year apart during natalizumab treatment. At baseline, patients were on natalizumab for (mean ± SD) 16.6 ± 10.9 months with age 38.5 ± 7.4 and disease duration 9.7 ± 4.3 years. RESULTS: At baseline, GMV was 664.0 ± 56.4 ml, Expanded Disability Status Scale (EDSS) score was 2.3 ± 2.0, timed 25-foot walk (T25FW) was 6.1±3.4 s; two patients (10%) had gadolinium (Gd)-enhancing lesions. At follow-up, GMV was 663.9 ± 60.2 mL; EDSS was 2.6 ± 2.1 and T25FW was 5.9 ± 2.9 s. One patient had a mild clinical relapse during the observation period (0.052 annualized relapse rate for the entire cohort). No patients had Gd-enhancing lesions at follow-up. Linear mixed-effect models showed no significant change in annualized GMV [estimated mean change per year 0.338 mL, 95% confidence interval -9.66, 10.34, p = 0.94)], GM fraction (p = 0.92), whole brain parenchymal fraction (p = 0.64), T2 lesion load (p = 0.64), EDSS (p = 0.26) or T25FW (p = 0.79). CONCLUSIONS: This pilot study shows no GM atrophy during one year of natalizumab MS therapy. We also did not detect any loss of whole brain volume or progression of cerebral T2 hyperintense lesion volume during the observation period. These MRI results paralleled the lack of clinical worsening.

Experience with long-term rituximab use in a multiple sclerosis clinic.

BACKGROUND: Rituximab is a monoclonal antibody directed at CD20 positive B-lymphocytes and a potential therapeutic option in the treatment of multiple sclerosis. The safety of recurrent dosing is not established. OBJECTIVES: The objective of this work was to report the experience of long-term rituximab administration in a comprehensive multiple sclerosis care clinic. METHODS: This was a single-center retrospective observational analysis of patients receiving rituximab for the treatment of multiple sclerosis from 2004 to 2015. Different dosing regimens were reviewed to determine whether frequency or dose may affect safety. CD19 and CD20 counts were collected to evaluate B-cell suppression during therapy. Relapses, magnetic resonance imaging activity and rituximab-related adverse events were collected by chart review and prospective database entry. RESULTS: Of 107 patients included, the average duration of treatment was 33.2 months. Seventy-seven patients received recurrent rituximab dosing after initiation. CD19/20 reconstitution occurred in approximately 20% of patients at 6 months, regardless of dosing strategy. Despite CD19/20 counts of 0, three patients had relapses or magnetic resonance imaging activity. Mostly mild side effects in relation to therapy were seen, with the exception of three patients requiring hospitalization for urinary tract infections. CONCLUSIONS: In our clinic population, rituximab was well tolerated and safe with recurrent administration.

A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity.

OBJECTIVE: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. METHODS: We performed a genome-wide association study in interferon-ß (IFNß)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. RESULTS: We found an association between rs9828519(G) and nonresponse to IFNß (pdiscovery = 4.43 × 10(-8)) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 × 10(-4)). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNγ, which is a proinflammatory molecule. INTERPRETATION: This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNß-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNß treatment.

Eosinophilic fasciitis-like disorder developing in the setting of multiple sclerosis therapy.

IMPORTANCE: Dimethyl fumarate received FDA approval in March 2013 for treatment of multiple sclerosis and has had a rapid uptake in the field due in large part to a favorable safety profile. Side effects of dimethyl fumarate include flushing, gastrointestinal discomfort, and peripheral eosinophilia. We report a case of eosinophilic fasciitis-like disorder occurring in the setting of oral dimethyl fumarate therapy. Eosinophilic fasciitis is rare and may be related to the peripheral eosinophilia known to occur with this medication. OBSERVATIONS: We present a case of a 36-year-old male treated with oral dimethyl fumarate for 16 weeks who developed a bilateral eosinophilic fasciitis-like disorder of the thighs. Magnetic resonance imaging revealed a fluid collection in the fascial plane and histopathologic examination revealed an inflammatory infiltrate with dermal and subcutaneous edema and sclerosis consistent with eosinophilic fasciitis. We discuss studies reporting peripheral eosinophilia with fumaric acid medications as well as the literature exploring possible mechanisms. CONCLUSIONS: With the anticipated widespread use of dimethyl fumarate for multiple sclerosis patients, it is important for practitioners to recognize the symptoms of eosinophilic fasciitis and be aware of a possible association of oral dimethyl fumarate treatment with the development of an eosinophilic fasciitis-like disorder.

An expanded composite scale of MRI-defined disease severity in multiple sclerosis: MRDSS2.

The objective of this study was to test a new version of the Magnetic Resonance Disease Severity Scale (MRDSS2), incorporating cerebral gray matter (GM) and spinal cord involvement from 3 T MRI, in modeling the relationship between MRI and physical disability or cognitive status in multiple sclerosis (MS). Fifty-five MS patients and 30 normal controls underwent high-resolution 3 T MRI. The patients had an Expanded Disability Status Scale score of 1.6±1.7 (mean±SD). The cerebral normalized GM fraction (GMF), the T2 lesion volume (T2LV), and the ratio of T1 hypointense LV to T2LV (T1/T2) were derived from brain images. Upper cervical spinal cord area (UCCA) was obtained from spinal cord images. A within-subject d-score (difference of MS from normal control) for each MRI component was calculated, equally weighted, and summed to form MRDSS2. With regard to the relationship between physical disability and MRDSS2 or its individual components, MRI-Expanded Disability Status Scale correlations were significant for MRDSS2 (r=0.33, P=0.013) and UCCA (r=-0.33, P=0.015), but not for GMF (P=0.198), T2LV (P=0.707), and T1/T2 (P=0.240). The inclusion of UCCA appeared to drive this MRI-disability relationship in MRDSS2. With regard to cognition, MRDSS2 showed a larger effect size (P=0.035) than its individual components [GMF (P=0.081), T2LV (P=0. 179), T1/T2 (P=0.043), and UCCA (P=0.818)] in comparing cognitively impaired with cognitively preserved patients (defined by the Minimal Assessment of Cognitive Function in MS). Both cerebral lesions (T1/T2) and atrophy (GMF) appeared to drive this relationship. We describe a new version of the MRDSS, which has been expanded to include cerebral GM and spinal cord involvement. MRDSS2 has concurrent validity with clinical status.

Iron and multiple sclerosis.

Iron is essential for normal cellular functioning of the central nervous system. Abnormalities in iron metabolism may lead to neuronal death and abnormal iron deposition in the brain. Several studies have suggested a link between brain iron deposition in normal aging and chronic neurologic diseases, including multiple sclerosis (MS). In MS, it is still not clear whether iron deposition is an epiphenomenon or a mediator of disease processes. In this review, the role of iron in the pathophysiology of MS will be summarized. In addition, the importance of conventional and advanced magnetic resonance imaging techniques in the characterization of brain iron deposition in MS will be reviewed. Although there is currently not enough evidence to support clinical use of iron chelation in MS, an overview of studies of iron chelation or antioxidant therapies will be also provided.

Role of immunosuppressive therapy for the treatment of multiple sclerosis.

Immunosuppressives have been used in multiple sclerosis (MS) since 1966. Today, we have many treatments for the relapsing forms of the disease, including 8 US Food and Drug Administration-approved therapies, with more soon to be introduced. Given the current treatment landscape what place do immunosuppressants have in combating MS? Trial work and our experience suggest that immunosuppressives still have an important role in treating MS. Cyclophosphamide finds use in treating patients with severe, inflammatory relapsing remitting MS or those suffering from a fulminant attack. We tend to employ mycophenolate mofetil as an add-on to injectable therapy for patients experiencing breakthrough activity. Some progressive (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) patients may stabilize after treatment with either cyclophosphamide or mycophenolate. We rarely employ mitoxantrone because of potential cardiac or carcinogenic effects. We prefer to use cyclophosphamide or mycophenolate mofetil in preference to methotrexate because evidence of efficacy is limited for this drug. We have less experience with azathioprine, but it may be an alternative for patients with limited options who are unable to tolerate conventional therapies.

The relationships among MRI-defined spinal cord involvement, brain involvement, and disability in multiple sclerosis.

OBJECTIVE: To determine the interrelationships between MRI-defined lesion and atrophy measures of spinal cord involvement and brain involvement and their relationships to disability in a small cohort of patients with multiple sclerosis (MS). BACKGROUND: Although it is known that cervical spinal cord atrophy correlates with disability in MS, it is unknown whether it is the most important determinant when compared to other regions of the central nervous system (CNS). Furthermore, it is not clear to what extent brain and cord lesions and atrophy are related. DESIGN AND METHODS: 3T MRI of the whole brain and whole spinal cord was obtained in 21 patients with MS, including 18 with relapsing-remitting, one with secondary progressive, one with primary progressive, and one with a clinically isolated syndrome. Brain global gray and white matter volumes were segmented with Statistical Parametric Mapping 8. Spinal cord contour volume was segmented in whole by a semi-automated method with bins assigned to either the cervical or thoracic regions. All CNS volumes were normalized by the intracranial volume. Brain and cord T2 hyperintense lesions were segmented using a semi-automated edge finding tool. RESULTS: Among all MRI measures, only upper cervical spinal cord volume significantly correlated with Expanded Disability Status Scale score (r =-.515, P = .020). The brain cord relationships between whole or regional spinal cord volume or lesions and gray matter, white matter, or whole brain volume or whole brain lesions were generally weak and all nonsignificant. CONCLUSIONS AND RELEVANCE: In this preliminary study of mildly disabled, treated MS patients, cervical spinal cord atrophy most strongly correlates with physical disability in MS when accounting for a wide range of other CNS measures of lesions and atrophy, including thoracic or whole spinal cord volume, and cerebral gray, white or whole brain volume. The weak relationship between spinal cord and brain lesions and atrophy may suggest that they progress rather independently in patients with MS.

Brain MRI lesion load at 1.5T and 3T versus clinical status in multiple sclerosis.

BACKGROUND/PURPOSE: To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI). METHODS: Brain MRI fluid-attenuated inversion-recovery (FLAIR) sequences were performed in 32 multiple sclerosis (MS) patients. Expanded Disability Status Scale (EDSS) score (mean±standard deviation) was 2±2.0 (range 0-8), disease duration 9.3±8.0 (range .8-29) years. RESULTS: FLAIR lesion volume (FLLV) at 3T was higher than at 1.5T (P=.01). Correlation between 1.5T FLLV and EDSS score was poor, while 3T FLLV correlated moderately and significantly (rs=.39, P=.03). When controlling for age and depression, correlations between FLLV and cognitive measures were significant at 1.5T for the Judgment of Line Orientation test (JLO) (rs=-.44, P=.05), the Symbol Digit Modalities Test (SDMT) (rs=-.49, P=.02), and the California Verbal Learning Test Delayed Free Recall (CVLT DR) (rs=-.44, P=.04). Correlations at 3T were also significant for these tests, but of greater magnitude: JLO (rs=-.70, P=.0005), SDMT (rs=-.73, P=.0001), CVLT DR (rs=-.061, P=.003). Additional significant correlations obtained only at 3T included the 2 second-paced auditory serial addition test (rs=-.55, P=.01), the Brief Visuospatial Memory Test-Delayed Free Recall (rs=-.56, P=.007), and the California Verbal Learning Test Total Recall (rs=-.42, P=.05). CONCLUSION: MRI at 3T may boost sensitivity and improve validity in MS brain lesion assessment.

Role of iron in neurotoxicity: a cause for concern in the elderly?

PURPOSE OF REVIEW: To explore the role of iron physiology in the brain of healthy adults and review how increased brain iron deposition has been associated with common neurodegenerative diseases that affect the elderly. RECENT FINDINGS: Because iron plays a role in oxygen transportation, myelin synthesis, neurotransmitter production, and electron transfers, it serves as a crucial cofactor in normal central nervous metabolism. However, an increased level of brain iron may promote neurotoxicity due to free radical formation, lipid peroxidation, and ultimately, cellular death. Advanced neuroimaging techniques and pathological studies have demonstrated increased brain iron with aging, and increased iron deposition has also been observed in patients with a constellation of neurological diseases, including Alzheimer's disease, Parkinson's disease, and stroke. SUMMARY: Pathologic and neurologic imaging coupled with experimentation have increased our understanding of the link between iron and neurodegeneration. A potential implication is that disease-modifying therapies aimed at removing excess iron may one day be part of the armamentarium employed by clinicians to decrease the burden of neurodegenerative diseases in the elderly.