Publications by authors named "Robert J Fox"

181 Publications

Vitamin D Levels and Visual System Measurements in Progressive Multiple Sclerosis: A Cross-sectional Study.

Int J MS Care 2021 Mar-Apr;23(2):53-58. Epub 2020 Apr 28.

Background: Vitamin D deficiency is associated with increased disease activity in multiple sclerosis (MS), but its role in progressive MS has not been elucidated. The objective was to determine the correlation between vitamin D levels and visual parameters in primary progressive MS (PPMS) and secondary progressive MS (SPMS).

Methods: Serum 25-hydroxyvitamin D (25[OH]D) and 25-hydroxyvitamin D (25[OH]D) levels were obtained from the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS). Visual function measurements and vitamin D associations were determined using the Pearson correlation and the generalized linear mixed model.

Results: The analysis included 258 patients (mean ± SD age of 55.6 ± 7.3 years, 52.7% female, and 52.3% PPMS). Mean vitamin D values were above sufficiency and were similar between PPMS and SPMS ( = .47 and = .31). There was no association between 25(OH)D levels and any visual markers, including peripapillary retinal nerve fiber layer thickness (Spearman = -0.08), macular volume ( = -0.03), ganglion cell-inner plexiform layer ( = -0.07), and 2.5% low-contrast visual acuity test ( = -0.10). No statistically significant associations between vitamin D levels and visual system measurements were detected in the PPMS and SPMS subgroups.

Conclusions: Vitamin D levels were not associated with optical coherence tomography findings or low-contrast letter acuity in this group of patients with progressive MS.
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http://dx.doi.org/10.7224/1537-2073.2020-005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047686PMC
April 2020

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.

JAMA Neurol 2021 Mar 29. Epub 2021 Mar 29.

Neurology and Research Center for Clinical Neuroimmunology and Neuroscience Basel, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering University Hospital and University of Basel, Basel, Switzerland.

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).

Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.

Design, Setting, And Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.

Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.

Main Outcomes And Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.

Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).

Conclusions And Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.

Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.
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http://dx.doi.org/10.1001/jamaneurol.2021.0405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008435PMC
March 2021

Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages.

Mult Scler 2021 Mar 22:1352458521999651. Epub 2021 Mar 22.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

Objective: Describe magnetic resonance imaging (MRI) susceptibility changes in progressive multifocal leukoencephalopathy (PML) and identify neuropathological correlates.

Methods: PML cases and matched controls with primary central nervous system lymphoma (PCNSL) were retrospectively identified. MRI brain at 3 T and 7 T were reviewed. MRI-pathology correlations in fixed brain autopsy tissue were conducted in three subjects with confirmed PML.

Results: With PML ( = 26 total, = 5 multiple sclerosis natalizumab-associated), juxtacortical changes on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences were noted in 3/3 cases on 7 T MRI and 14/22 cases (63.6%) on 1.5 T or 8/22 (36.4%) 3 T MRI. Similar findings were only noted in 3/25 (12.0%) of PCNSL patients (odds ratio (OR) 12.83, 95% confidence interval (CI), 2.9-56.7, < 0.001) on 1.5 or 3 T MRI. On susceptibility sequences available prior to diagnosis of PML, 7 (87.5%) had changes present on average 2.7 ± 1.8 months (mean ± SD) prior to diagnosis. Postmortem 7 T MRI showed SWI changes corresponded to areas of increased iron density along the gray-white matter (GM-WM) junction predominantly in macrophages.

Conclusion: Susceptibility changes in PML along the GM-WM junction can precede noticeable fluid-attenuated inversion recovery (FLAIR) changes and correlates with iron accumulation in macrophages.
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http://dx.doi.org/10.1177/1352458521999651DOI Listing
March 2021

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.

JAMA Neurol 2021 Mar 19. Epub 2021 Mar 19.

Washington University School of Medicine in St Louis, St Louis, Missouri.

Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections.

Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS.

Design, Setting, And Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing.

Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19.

Main Outcomes And Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death.

Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]).

Conclusions And Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.
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http://dx.doi.org/10.1001/jamaneurol.2021.0688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980147PMC
March 2021

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis.

Mult Scler 2021 Feb 26:1352458520986956. Epub 2021 Feb 26.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS.

Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS.

Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable.

Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were  = 0.52 and  = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum ( = 0.76) or CSF ( = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed.

Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.
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http://dx.doi.org/10.1177/1352458520986956DOI Listing
February 2021

Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS.

Neurol Clin Pract 2020 Dec;10(6):510-519

Department of Neurology (AC), Inselspital, Bern University Hospital, University of Bern, Switzerland; Division of Neuroimmunology and Neurovirology (JR), University of Utah, Salt Lake City, UT; Brain Institute (JR), University of Utah, Salt Lake City, UT; Department of Neurology (JR), University of Utah, Salt Lake City, UT; Rocky Mountain Multiple Sclerosis Center at the University of Colorado (EA), Aurora, CO; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (AB-O), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Children's Hospital of Philadelphia (AB-O), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Central Clinical School (HB), Monash University, VIC, Australia; Mellen Center for Multiple Sclerosis Treatment and Research (RJF), Cleveland Clinic, OH; Department of Neurology (RG), St. Josef-Hospital, Ruhr University Bochum, Germany; South Shore Neurologic Association PC (MG), Patchogue, NY; Eastern Health MS Service (JH), Box Hill, VIC, Australia; Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital (TS), University of Melbourne, Parkville, VIC, Australia; Department of Neurology and Neurotherapeutics (KW), University of Texas Southwestern Medical Center, Multiple Sclerosis and Neuroimmunology Imaging Program, Clinical Center for Multiple Sclerosis, Dallas, TX; Department of Neuroscience (DF, PS), Neurology Unit, Azienda Ospedaliera Universitaria, Modena, Italy; Liverpool Hospital (SH), NSW, Australia; Department of Medicine (TK), CORe Unit, University of Melbourne, VIC, Australia; Department of Neurology (TK), Royal Melbourne Hospital, VIC, Australia; School of Medicine and Public Health (JL-S), University Newcastle, NSW, Australia; Department of Neurology (JL-S), John Hunter Hospital, Hunter New England Health, Newcastle, NSW, Australia; Department of Neurology (C. McGuigan), St. Vincent's University Hospital and University College, Dublin, Ireland; Envision Pharma Group (KS), Fairfield, CT; and Biogen (CC, SF, FW, C. Miller), Cambridge, MA.

Background: Delayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF.

Methods: Data sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation.

Results: The majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC ≥0.8 × 10/L was 2-4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC ≥0.91 × 10/L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation; rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for ≥3 years, lymphocyte reconstitution to ≥0.91 × 10/L was 12-18 months vs 2-3 months in patients with lymphopenia persisting <6 months.

Conclusions: The majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2-4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.
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http://dx.doi.org/10.1212/CPJ.0000000000000800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837440PMC
December 2020

Response to ibudilast treatment according to progressive multiple sclerosis disease phenotype.

Ann Clin Transl Neurol 2021 01 18;8(1):111-118. Epub 2021 Jan 18.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio, USA.

Objective: Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis.

Background: Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown.

Design/methods: SPRINT-MS was a randomized, placebo-controlled 96-week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three-way interaction linear-mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored.

Results: Analysis showed that there was a three-way interaction between the time, treatment effect, and disease phenotype (P < 0.06). After further inspection, the overall treatment effect was primarily driven by patients with PPMS (P < 0.01), and not by patients with SPMS (P = 0.97). This difference may have been due to faster brain atrophy progression seen in the PPMS placebo group compared to SPMS placebo (P < 0.02). Although backward selection (P < 0.05) retained age, T2 lesion volume, RNFL, and longitudinal diffusivity as significant baseline covariates in the linear-mixed model, the adjusted overall treatment effect was still driven by PPMS (P < 0.01).

Interpretation: The previously reported overall treatment effect of ibudilast on worsening of brain atrophy in progressive MS appears to be driven by patients with PPMS that may be, in part, because of the faster atrophy progression rates seen in the placebo-treated group.
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http://dx.doi.org/10.1002/acn3.51251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818089PMC
January 2021

Importance of incorporating quantitative imaging biomarker technical performance characteristics when estimating treatment effects.

Clin Trials 2021 Apr 10;18(2):197-206. Epub 2021 Jan 10.

Oregon Health Science University, Portland, OR, USA.

Background/aims: Quantitative imaging biomarkers have the potential to detect change in disease early and noninvasively, providing information about the diagnosis and prognosis of a patient, aiding in monitoring disease, and informing when therapy is effective. In clinical trials testing new therapies, there has been a tendency to ignore the variability and bias in quantitative imaging biomarker measurements. Unfortunately, this can lead to underpowered studies and incorrect estimates of the treatment effect. We illustrate the problem when non-constant measurement bias is ignored and show how treatment effect estimates can be corrected.

Methods: Monte Carlo simulation was used to assess the coverage of 95% confidence intervals for the treatment effect when non-constant bias is ignored versus when the bias is corrected for. Three examples are presented to illustrate the methods: doubling times of lung nodules, rates of change in brain atrophy in progressive multiple sclerosis clinical trials, and changes in proton-density fat fraction in trials for patients with nonalcoholic fatty liver disease.

Results: Incorrectly assuming that the measurement bias is constant leads to 95% confidence intervals for the treatment effect with reduced coverage (<95%); the coverage is especially reduced when the quantitative imaging biomarker measurements have good precision and/or there is a large treatment effect. Estimates of the measurement bias from technical performance validation studies can be used to correct the confidence intervals for the treatment effect.

Conclusion: Technical performance validation studies of quantitative imaging biomarkers are needed to supplement clinical trial data to provide unbiased estimates of the treatment effect.
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http://dx.doi.org/10.1177/1740774520981934DOI Listing
April 2021

Comparative responsiveness of the health utilities index and the RAND-12 for multiple sclerosis.

Mult Scler 2021 Jan 5:1352458520981370. Epub 2021 Jan 5.

Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, USA.

Background: Outcome measures need to be valid and have good test-retest reliability and responsiveness. We compared the responsiveness of the RAND-12 and the Health Utilities Index-mark III (HUI3) in persons with multiple sclerosis (MS).

Methods: In Spring 2018 and 2019, North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants completed the HUI3, the RAND-12, and reported disability (Patient Determined Disease Steps (PDDS)) and employment status (full-time, part-time, and no). We used changes in PDDS and employment status as anchors. We assessed responsiveness using effect size, standardized response mean, and the responsiveness index. We used relative efficiency (RE) to compare the responsiveness of the health-related quality of life (HRQOL) scores, adjusting for sociodemographic factors.

Results: We included 4769 participants in the analysis. They had a mean (standard deviation (SD)) age of 60.9 (10.1) years, and 3826 participants (80.2%) were women. RE was highest for the HUI3 for changes in in disability status (HUI3: 1.0, Physical Component Score-12 (PCS-12): 0.80, and Mental Component Score-12 (MCS-12): 0.41) and for changes in employment status (HUI3: 1.0, PCS-12: 0.70, and MCS-12: 0.17).

Conclusion: The HUI3 was more responsive to changes in disability and employment status than the PCS-12 or MCS-12. Given the HUI3's other strong psychometric properties, it may be the preferred generic measure of HRQOL in MS.
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http://dx.doi.org/10.1177/1352458520981370DOI Listing
January 2021

Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review.

JAMA Neurol 2021 Mar;78(3):351-364

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e di Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS.

Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS.

Conclusions And Relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.
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http://dx.doi.org/10.1001/jamaneurol.2020.4689DOI Listing
March 2021

Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study.

Neurology 2021 01 2;96(4):e491-e500. Epub 2020 Dec 2.

From Washington University (R.T.N.), St. Louis, MO; Cleveland Clinic Foundation (R.A.B., K.N., C.G., R.J.F.), OH; University of Iowa (C.S.C., J.F., J.Y., E.K.), Iowa City; University of Rochester (A.D.G.), NY; Massachusetts General Hospital (M.K., E.C.K.), Harvard Medical School, Boston; McConnell Brain Imaging Centre (S.N.), Montreal Neurological Institute, McGill University; and NeuroRx Research (S.N.), Montreal, Canada.

Objective: To determine whether ibudilast has an effect on brain volume and new lesions in progressive forms of multiple sclerosis (MS).

Methods: A randomized, placebo-controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive MS. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by structural image evaluation, using normalization, of atrophy (SIENA) was a sensitivity analysis.

Results: A total of 129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo ( = 0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo ( = 0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs placebo ( = 0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo ( = 0.08).

Conclusion: Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to affect markers associated with neurodegenerative processes, but not inflammatory processes.

Classification Of Evidence: This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions or new T1 lesions.
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http://dx.doi.org/10.1212/WNL.0000000000011314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905793PMC
January 2021

Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis.

Mult Scler 2020 Nov 18:1352458520971819. Epub 2020 Nov 18.

Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland.

Background: In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.

Objective: To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.

Methods: Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.

Results: Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.

Conclusion: By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
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http://dx.doi.org/10.1177/1352458520971819DOI Listing
November 2020

Optical coherence tomography outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive multiple sclerosis.

Mult Scler 2020 Oct 15:1352458520964409. Epub 2020 Oct 15.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA.

Background: The SPRINT-MS trial demonstrated benefit of ibudilast on brain atrophy over 96 weeks in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) was performed in all trial participants.

Objective: Report the OCT results of the SPRINT-MS trial.

Methods: OCT was obtained at baseline and every 6 months using spectral domain OCT and analyzed by an OCT reading center. Change in each OCT outcome measure by treatment group was estimated using linear mixed models.

Results: Change in pRNFL thickness was +0.0424 uM/year (95% confidence interval (CI): -0.3091 to 0.3939) for ibudilast versus -0.2630 uM (95% CI: -0.5973 to 0.0714) for placebo ( = 244,  = 0.22). Macular volume change was -0.00503 mm/year (-0.02693 to 0.01688) with ibudilast versus -0.03659 mm/year (-0.05824 to -0.01494) for placebo in the Spectralis cohort ( = 61,  = 0.044). For the Cirrus cohort, macular volume change was -0.00040 mm/year (-0.02167, 0.020866) with ibudilast compared to -0.02083 mm/year (-0.04134 to -0.00033) for placebo ( = 183,  = 0.1734). Ganglion cell-inner plexiform layer thickness change, available from Cirrus, was -0.4893 uM/year (-0.9132, -0.0654) with ibudilast versus -0.9587 uM/year (-1.3677, -0.5498) with placebo ( = 183,  = 0.12).

Conclusion: Retinal thinning in MS may be attenuated by ibudilast. Sample size estimates suggest OCT can be a viable outcome measure in progressive MS trials if a therapy has a large treatment effect.

Trial Registration: NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.
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http://dx.doi.org/10.1177/1352458520964409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046841PMC
October 2020

Serum neurofilament light as a biomarker in progressive multiple sclerosis.

Neurology 2020 09 16;95(10):436-444. Epub 2020 Jul 16.

From the University College London (R.K.), United Kingdom; National Multiple Sclerosis Society (K.E.S., M.A.), New York; McGill University (D.L.A.), Montreal, Canada; Perron Institute (W.C.), Sir Charles Gairdner Hospital, Perth, Australia; University Hospital Vall d'Hebron (M.C.), Barcelona, Spain; San Raffaele Scientific Institute (R.F.), Milan, Italy; Genentech/Roche (C.H.), South San Francisco; University Hospital Basel (J.K., D.L.), Switzerland; Biogen (T.P.), Boston; Quanterix Corporation (T.P.), Billerica; Rigshospitalet (F.S.), University of Copenhagen, Denmark; Progressive Multiple Sclerosis Alliance (C.S.), Glasgow, United Kingdom; Amsterdam UMC (C.E.T.), the Netherlands; MedDay Pharma (I.T.), Paris, France; Novartis (F.v.R.), Basel, Switzerland; Elizabeth Walker Consulting (E.W.), Seattle; and Mellen Center for Multiple Sclerosis (R.J.F.), Cleveland Clinic.

There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.
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http://dx.doi.org/10.1212/WNL.0000000000010346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538221PMC
September 2020

Patient reported outcomes and performance metrics at diagnosis of secondary progressive multiple sclerosis.

Mult Scler 2021 Apr 16;27(5):742-754. Epub 2020 Jul 16.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Background: Relapsing-remitting multiple sclerosis (RRMS) usually evolves into secondary progressive multiple sclerosis (SPMS). Recognition of SPMS is important because of prognostic and treatment implications.

Objective: The objective of this study is to determine distributions of patient-reported outcomes (PROs) and the Timed 25-Foot Walk (T25FW) at SPMS diagnosis and describe the evolution of these metrics in patients with SPMS.

Methods: A tertiary MS center clinical database was queried to identify patients with RRMS and SPMS. PRO data including performance scales (PS), Patient Health Questionnaire-9 (PHQ-9), European Quality of Life-5-Dimensions (EQ-5D), and the T25FW were extracted. Descriptive statistics were calculated at SPMS diagnosis, and score trajectories were modeled. Cox proportional hazards modeling was used to estimate hazard ratios for time to SPMS diagnosis.

Results: Among 5,558 patients identified, 164 were diagnosed with SPMS between January 2008 and June 2016. At SPMS diagnosis, the mean outcome values were T25FW = 12.5 seconds (standard deviation, SD = 10.7), PS = 15.6 (SD = 6.5), PHQ-9 = 6.8 (SD = 4.2), and EQ-5D = 0.63 (SD = 0.20). Distinct patterns were observed in the measures leading up to SPMS diagnosis. Higher age, male gender, longer disease duration, and greater disability were associated with an increased hazard of SPMS diagnosis.

Conclusion: Longitudinal monitoring of PROs and performance metrics may help identify those at higher risk of near-term SPMS.
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http://dx.doi.org/10.1177/1352458520936214DOI Listing
April 2021

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

Neurol Clin Pract 2020 Jun;10(3):222-231

Mellen Center for Multiple Sclerosis (GM, BPM, LEB, MW, MA, FB, AB, DC, DSC, CF, RJF, SG, BG, CH-C, KRM, MPM, DMM, MN, AR-G, MR, HY, MAW, DO, JAC, RAB), Neurological Institute, Cleveland Clinic Foundation; Department of Quantitative Health Sciences (HL), Cleveland Clinic; Schey Center for Cognitive Neuroimaging (SMR), Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic Foundation; Department of Biomedical Engineering (DS, JLA), Lerner Research Institute, Cleveland Clinic Foundation, OH; and Epic Systems Corporation (NJ), Verona, WI.

Background: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice.

Method: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments.

Results: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates.

Conclusions: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.
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http://dx.doi.org/10.1212/CPJ.0000000000000710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292568PMC
June 2020

Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE.

Ther Adv Neurol Disord 2020 12;13:1756286420915005. Epub 2020 May 12.

Biogen, 225 Binney Street, Cambridge, MA 02142, USA.

Introduction: We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported.

Methods: Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0-2 /DMF for years 3-9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed.

Results: Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0-2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6-0.8 and 0.9-2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was -1.32% (range -1.60% to -1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 10/L at discontinuation ( = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation.

Conclusions: Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS.

Trial Registration: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).
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http://dx.doi.org/10.1177/1756286420915005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222239PMC
May 2020

The window of opportunity for treatment of progressive multiple sclerosis.

Curr Opin Neurol 2020 06;33(3):262-270

Institute of Experimental Neurology, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.

Purpose Of Review: Based on the knowledge of disease mechanisms in the progressive course of multiple sclerosis and the experience from randomized clinical trials, we assessed the timing of disease-modifying therapy in patients with progressive multiple sclerosis to define the optimal window of opportunity for treatment of progressive multiple sclerosis.

Recent Findings: In progressive multiple sclerosis both small molecules that cross the blood--brain barrier (siponimod) and monoclonal antibodies (ocrelizumab) have shown therapeutic efficacy and have been approved for treatment of progressive multiple sclerosis. However, the majority of phase II and phase III trials in progressive forms of multiple sclerosis have been negative, probably owing to either late start of treatment or use of drugs that are ineffective for treatment of progressive multiple sclerosis.

Summary: Results from phase II and III trials suggest that the window of opportunity for treatment of progressive multiple sclerosis with anti-inflammatory drugs is predominantly in the early phase of the progressive disease course when patients have lower age, shorter duration of progressive multiple sclerosis, and more pronounced clinical and MRI inflammatory activity. Ongoing trials of neuroprotective drugs may widen the window of opportunity by expanding targeted pathophysiologies.
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http://dx.doi.org/10.1097/WCO.0000000000000811DOI Listing
June 2020

Fourteen-year serial MRIs of patients with mild and severe courses of MS.

Neurol Clin Pract 2020 Feb;10(1):e5-e6

Department of Biomedical Engineering (KN, EF), Lerner Research Institute, Cleveland Clinic; Mellen Center for Multiple Sclerosis Treatment and Research (RAR, DO, RJF), Neurological Institute, Cleveland Clinic; and Department of Neurosciences (BDT), Lerner Research Institute, Cleveland Clinic, OH. Dr. Rudick is now with Biogen, Cambridge, MA.

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http://dx.doi.org/10.1212/CPJ.0000000000000695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057063PMC
February 2020

Gender identity and sexual orientation affect health care satisfaction, but not utilization, in persons with Multiple Sclerosis.

Mult Scler Relat Disord 2020 Jan 12;37:101440. Epub 2019 Oct 12.

Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. Electronic address:

Objective: We aimed to determine the association between gender identity and sexual orientation on health care utilization in persons with multiple sclerosis (MS), as well as satisfaction with their doctor and comfort discussing sexual health with their doctor.

Methods: We surveyed participants from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding their gender identity and sexual orientation in 2017. Participants also reported their sociodemographic characteristics, disability status, health behaviors and health care utilization, including whether any hospitalizations or emergency room (ER) visits occurred or any disease-modifying therapy (DMT) was used within the last six months. We compared the likelihood of hospitalizations, ER visits and DMT use between (i) cisgender and transgender participants; and (ii) heterosexual, homosexual, and "other sexual orientation" participants using multivariable logistic regression models adjusting for potential confounding factors.

Results: Of the 5,604 eligible responders, 1168 (20.8%) reported their sex at birth as male and 4436 reported their sex at birth as female (79.2%). Twenty-five (0.45%) participants identified as transgender and 260 (4.6%) as non-heterosexual individuals. As compared to participants who reported their sexual orientation as heterosexual, non-heterosexual participants were younger, with an earlier age at MS symptom onset, more likely to have a post-secondary education, and more likely to be single. The frequency of any ER visits, any hospital admissions, and DMT use did not differ according to gender identity did not differ according to gender identity or sexual orientation. As compared to cisgender participants, transgender participants reported less comfort (p < 0.042) discussing sexual health with their doctor; findings were similar for non-heterosexual participants as compared to heterosexual participants. Participants reporting other sexual orientation also reported lower satisfaction (p < 0.039) with their doctor than other participants.

Conclusion: Gender identity and sexual orientation were not associated with differences in healthcare utilization in persons with MS. However, health care experiences and satisfaction with care may be altered by gender identity and sexual orientation.
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http://dx.doi.org/10.1016/j.msard.2019.101440DOI Listing
January 2020

Feast or famine in multiple sclerosis therapeutics.

Authors:
Robert J Fox

Lancet Neurol 2020 03 22;19(3):196-197. Epub 2020 Jan 22.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(19)30487-9DOI Listing
March 2020

New applications for independent activities of daily living in measuring disability in multiple sclerosis.

Mult Scler 2021 01 14;27(1):97-106. Epub 2020 Jan 14.

Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Background: Disability outcome measures in multiple sclerosis (MS) focus heavily on ambulation; however, limitations in performing everyday activities encompass another type of disability.

Objectives: The aim of this study was to examine the ability of instrumental activities of daily living (IADL) scale to discriminate between different levels of disability and to predict disability progression.

Methods: The North American Research Committee on Multiple Sclerosis (NARCOMS) registry fall 2006 semi-annual survey asked participants to complete the RAND-12, Performance Scales, Patient Determined Disease Steps (PDDS), and IADL questionnaires. We modeled the trajectory of disability change, using the PDDS, over 12 years. Analyses used linear and repeated measures regression methods.

Results: Of respondents ( = 9931), 9559 (96%) completed the PDDS and IADL scale. Respondents were mostly female (76%), Caucasian (92%), and 52.3 (10.5) years old with moderate disability (median PDDS 4 (early cane)). Mean (SD) IADL total score was 20.5 (3.7). Discriminant ability of the IADL scale was higher than other measures considered at higher levels of disability. Adjusted longitudinal models showed that needing greater assistance on IADLs was independently predictive of trajectories of greater disability change.

Conclusion: IADL scale had a greater ability to discriminate between higher disability levels than RAND-12 domains. The IADL scale may provide a useful and clinically relevant tool to measure disability in progressive MS populations.
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http://dx.doi.org/10.1177/1352458519898591DOI Listing
January 2021

Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and fingolimod at 36-month follow-up.

J Neurol Sci 2019 Dec 15;407:116498. Epub 2019 Oct 15.

Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States. Electronic address:

Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). There are currently no known head-to-head studies comparing DMF and FTY over 36 months, which leaves their relative effectiveness unknown.

Objective: To assess real-world discontinuation, effectiveness, and switching practices of DMF and FTY over 36 months along with disease activity after switching DMT.

Methods: Patients prescribed DMF (n = 737) and FTY (n = 535) from two academic MS centers were retrospectively reviewed. Discontinuation and effectiveness outcomes were assessed using propensity score (PS) weighting. PS model covariates included sociodemographics and clinical and MRI characteristics.

Results: Discontinuation was more common in DMF (58.3%) versus FTY (45.2%) over 36 months [OR = 1.81, 95% CI (1.41-2.31), p < .001], largely driven by intolerance [OR = 1.63, 95% CI (1.18-1.73), p < .001]. There were no differences in clinical relapses [OR = 1.27, 95% CI (0.90-1.79), p = .17], gadolinium-enhancing (GdE) lesions [OR = 1.25, 95% CI (0.85-1.84), p = .26], or new T2-hyperintense lesions [OR = 0.99, 95% CI (0.74-1.32), p = .93]. Within 12 months of DMF/FTY discontinuation, switchers to highly effective therapy (HET) versus other DMTs (injectables/orals) had fewer relapses (DMF/HET, 5.9% versus DMF/Other, 14.2%, p = .03; FTY/HET, 11.6% versus FTY/Other, 18.0%, p = .04) and fewer GdE lesions post-FTY (DMF/HET, 10.3% versus DMF/Other, 14.3%, p = .36; FTY/HET, 11.9% versus FTY/Other, 21.5%, p = .04).

Conclusion: This combined analysis showed similar effectiveness for DMF and FTY over 36 months with higher DMF discontinuations. Disease activity was lower in switchers to HET versus injectable/oral therapies after DMF/FTY cessation.
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http://dx.doi.org/10.1016/j.jns.2019.116498DOI Listing
December 2019

Vitamin D and MRI measures in progressive multiple sclerosis.

Mult Scler Relat Disord 2019 Oct 13;35:276-282. Epub 2019 Aug 13.

Mellen Center for Multiple Sclerosis, Cleveland Clinic Foundation, Cleveland, OH, USA. Electronic address:

Background: Vitamin D deficiency is a proposed risk factor for multiple sclerosis (MS), but its role in progressive MS is not well understood.

Objective: To examine the association between vitamin D levels and MRI features in primary progressive (PPMS) and secondary progressive MS (SPMS).

Methods: Serum 25-hydroxyvitamin D (25[OH]D) and 25-hydroxyvitamin D (25[OH]D) levels were obtained from 267 subjects enrolled into the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis (SPRINT-MS). Associations between imaging data and vitamin D levels was determined using Pearson or Spearman correlation and multivariate regression analyses.

Results: 267 patients (age 55.6 ± 7.4, 47.2% male, and 51.3% PPMS) were evaluated with quantitative MRI and vitamin D levels. 25(OH)D and 25(OH)D were similar between PPMS and SPMS. There was no significant association between vitamin D and T1/2 lesion volume and brain parenchymal fraction. Modest associations were found between 25(OH)D and whole brain-magnetization transfer ratio (WB-MTR, r = 0.17, p = 0.007) and normal appearing grey matter MTR (NAGM-MTR, r = 0.15, p = 0.02).

Conclusions: 25(OH)D levels were not associated with brain volume or lesional measures in progressive MS contrary to what has been described in relapsing remitting MS. An association between WB-MTR and NAGM-MTR suggest higher vitamin D levels may exert a protective role on myelin content in progressive MS.
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http://dx.doi.org/10.1016/j.msard.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830523PMC
October 2019

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis.

J Vis Exp 2019 07 19(149). Epub 2019 Jul 19.

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic;

We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 days a year. Participants consent to donate their brain and spinal cord. Most patients were followed by neurologists at the Cleveland Clinic Mellen Center for MS Treatment and Research. Their clinical courses and neurological disabilities are well-characterized. Soon after death, the body is transported to the MS Imaging Center, where the brain is scanned in situ by 3 T magnetic resonance imaging (MRI). The body is then transferred to the autopsy room, where the brain and spinal cord are removed. The brain is divided into two hemispheres. One hemisphere is immediately placed in a slicing box and alternate 1 cm-thick slices are either fixed in 4% paraformaldehyde for two days or rapidly frozen in dry ice and 2-methylbutane. The short-fixed brain slices are stored in a cryopreservation solution and used for histological analyses and immunocytochemical detection of sensitive antigens. Frozen slices are stored at -80 °C and used for molecular, immunocytochemical, and in situ hybridization/RNA scope studies. The other hemisphere is placed in 4% paraformaldehyde for several months, placed in the slicing box, re-scanned in the 3 T magnetic resonance (MR) scanner and sliced into centimeter-thick slices. Postmortem in situ MR images (MRIs) are co-registered with 1 cm-thick brain slices to facilitate MRI-pathology correlations. All brain slices are photographed and brain white-matter lesions are identified. The spinal cord is cut into 2 cm segments. Alternate segments are fixed in 4% paraformaldehyde or rapidly frozen. The rapid procurement of postmortem MS tissues allows pathological and molecular analyses of MS brains and spinal cords and pathological correlations of brain MRI abnormalities. The quality of these rapidly-processed postmortem tissues (usually within 6 h of death) is of great value to MS research and has resulted in many high-impact discoveries.
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http://dx.doi.org/10.3791/59511DOI Listing
July 2019

Perspectives of individuals with multiple sclerosis on discontinuation of disease-modifying therapies.

Mult Scler 2020 10 1;26(12):1581-1589. Epub 2019 Aug 1.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA.

Background: Therapeutic research in multiple sclerosis (MS) has focused on the development of treatments with little investigation regarding the possibility of discontinuation of disease-modifying therapies (DMTs).

Objective: To understand the opinion of individuals with MS concerning stopping DMTs and the factors that influence the decision-making process.

Methods: A mixed method approach was used starting with three focus groups from which a survey was developed. This survey was sent to 1000 participants in the North American Research Committee on Multiple Sclerosis registry who met inclusion criteria (age ⩾45 years; on most recent DMT for ⩾5 years). Descriptive analysis and structural equation modeling were used.

Results: Of 1000 participants receiving the survey, 377 provided complete responses and met inclusion criteria. Only 11.9% of participants reported that if their disease was considered stable, they would consider coming off medications. A high level of external locus of control in influential others such as physicians significantly decreased the likelihood of considering discontinuation.

Conclusions: Most individuals with MS report being unlikely to consider stopping MS therapy if their disease was considered "non-active." As the results of studies concerning DMT discontinuation are obtained, information from providers will be an important part of individuals' decision-making process.
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http://dx.doi.org/10.1177/1352458519867314DOI Listing
October 2020

Demyelinating lesions and progressive MS: Location, location, location.

Neurology 2019 08 9;93(7):283-284. Epub 2019 Jul 9.

Division of Neurology (E.A.Y.), Department of Pediatrics, Division of Neuroscience and Mental Health, SickKids Research Institute, Hospital for Sick Children, and University of Toronto, Ontario, Canada; and Mellen Center for Multiple Sclerosis (R.J.F.), Neurological Institute, Cleveland Clinic, OH.

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http://dx.doi.org/10.1212/WNL.0000000000007933DOI Listing
August 2019

The FLUOX-PMS trial: Underestimating the challenge in progressive multiple sclerosis trials.

Mult Scler 2019 11 20;25(13):1697-1699. Epub 2019 Jun 20.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1177/1352458519856985DOI Listing
November 2019

Outcomes of natalizumab treatment within 3 years of relapsing-remitting multiple sclerosis diagnosis: a prespecified 2-year interim analysis of STRIVE.

BMC Neurol 2019 Jun 8;19(1):116. Epub 2019 Jun 8.

Biogen, 225 Binney St, Cambridge, MA, 02142, USA.

Background: STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS.

Methods: Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions.

Results: The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores.

Conclusions: These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect.

Trial Registration: clinicaltrials.gov, NCT01485003 , registered 5 December 2011.
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http://dx.doi.org/10.1186/s12883-019-1337-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555913PMC
June 2019

Developing a crosswalk between the RAND-12 and the health utilities index for multiple sclerosis.

Mult Scler 2020 08 4;26(9):1102-1110. Epub 2019 Jun 4.

Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, USA.

Background: Researchers studying health-related quality of life (HRQOL) in multiple sclerosis (MS) can choose from many instruments, but findings from studies which use different instruments cannot be easily combined. We aimed to develop a crosswalk that associates scores from the RAND-12 to scores on the Health Utilities Index-Mark III (HUI3) in persons with MS.

Methods: In 2018, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry completed the RAND-12 and the HUI3 to assess HRQOL. We used item-response theory (IRT) and equipercentile linking approaches to develop a crosswalk between instruments. We compared predicted scores for the HUI3 from each crosswalk to observed scores using Pearson correlations, intraclass correlation coefficients (ICCs), and Bland-Altman plots.

Results: Of 11,389 invited participants, 7129 (62.6%) responded. Predicted and observed values of the HUI3 from the IRT-linking method were moderately correlated (Pearson  = 0.76) with good concordance (ICC = 0.72). However, the Bland-Altman plots suggested biased prediction. Predicted and observed values from the equipercentile linking method were also moderately correlated (Pearson  = 0.78, ICC = 0.78). The Bland-Altman plots suggested no bias.

Conclusion: We developed a crosswalk between the RAND-12 and the HUI3 in the MS population which will facilitate data harmonization efforts.
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http://dx.doi.org/10.1177/1352458519852722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412875PMC
August 2020