Publications by authors named "Enrique Alvarez"

133 Publications

Movement compensations during a step ascent task are associated with stair climbing performance in people with multiple sclerosis.

Gait Posture 2021 Apr 15;87:27-32. Epub 2021 Apr 15.

Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Background: The biomechanical mechanisms underlying stair climbing limitations are poorly understood in people with multiple sclerosis (MS).

Research Questions: Are trunk and pelvis motion and lower extremity joint moments during step ascent different between MS and control groups? Are step ascent biomechanics and stair climbing performance associated in people with MS?

Methods: 20 people with MS (49 ± 12 years, EDSS range: 1.5-5.5) and ten control participants (48 ± 12 years) underwent three-dimensional motion analysis while ascending a 15.2-cm step and also completed a timed Functional Stair Test. Main effects of group (MS vs Control) and limb (Stronger/Dominant vs Weaker/Non-dominant) and interactions were assessed using two-way analyses of variance. Associations between movement patterns during the step ascent and Functional Stair Test performance were performed using Pearson's correlations and backward stepwise linear regression.

Results: Significant group main effects were observed in greater sagittal pelvis excursion (p < 0.001), greater sagittal (p = 0.013) and frontal (p = 0.001) trunk excursion, and lower trail limb peak ankle plantar flexion moment (p < 0.001) of the MS group. Significant limb main effects were observed with greater sagittal trunk excursion (p = 0.037) and peak trail limb ankle plantar flexion moment (p = 0.037) in the stronger/dominant limb. A significant interaction was observed in peak knee extensor moment (p = .002). Stair climbing performance in the MS group correlated with sagittal (r = .607, p=<0.001) and frontal pelvis excursions (r = 0.385, p = 0.014), sagittal trunk excursion (r = .411, p = 0.008), and ankle plantar flexion moments (r=-0.415, p = 0.008). Sagittal and frontal pelvis excursion and bilateral handrail use explained a significant amount of variability in stair climbing performance (Adj R = 0.775).

Significance: In conclusion, despite the presence of proximal and distal lower extremity movement pattern compensations during a step ascent task, larger pelvis angular excursions are associated with impaired stair climbing performance in people with MS and may serve as targets for future rehabilitation interventions.
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http://dx.doi.org/10.1016/j.gaitpost.2021.04.022DOI Listing
April 2021

Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts.

Sci Rep 2021 Mar 29;11(1):7064. Epub 2021 Mar 29.

Department of Medical Oncology, Hospital General Universitario Gregorio Marañón Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), CIBERONC, Universidad Complutense, Dr Esquerdo 46, 28007, Madrid, Spain.

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.
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http://dx.doi.org/10.1038/s41598-021-85962-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007714PMC
March 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

Pandemic forward: Lessons learned and expert perspectives on multiple sclerosis care in the COVID-19 era.

Mult Scler Relat Disord 2021 04 24;49:102715. Epub 2020 Dec 24.

Icahn School of Medicine at Mount Sinai, 5 East 98th Street; Box 1138 New York, NY, 10029 USA. Electronic address:

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http://dx.doi.org/10.1016/j.msard.2020.102715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832784PMC
April 2021

Brain Atrophy Rates for Stable Multiple Sclerosis Patients on Long-Term Fingolimod versus Glatiramer Acetate.

Front Neurol 2020 23;11:1045. Epub 2020 Sep 23.

Department of Neurology, University of Colorado and Rocky Mountain Multiple Sclerosis Center at the University of Colorado, Aurora, CO, United States.

Clinically stable multiple sclerosis (MS) patients on long-term therapy often have negligible acute inflammation on MRI. Brain atrophy may provide insight into subclinical disease progression in such populations. This study aims to compare brain atrophy for age- and gender-matched MS patients treated for >2 years with fingolimod (FTY) or glatiramer acetate (GA), examining brain volume, cognition, and patient-reported outcomes (PROs). Stable relapsing-MS patients, age 18-60, on FTY or GA for >2 years were followed up for 2 years. MRI brain and lesion volumes, cognitive measures, and PROs were collected at baseline and annually. Forty-four FTY and forty-three GA patients completed baseline and year 2 visits. No differences in age, gender, or education were observed. Median EDSS was 2.0 and 2.5 ( = 0.22). Treatment duration was longer for GA, 6.50 vs. 3.73 years ( < 0.001). Baseline geometric mean T2LV were different, GA = 1,009.29 cm vs. FTY = 2,404.67 cm ( = 0.0071). Baseline brain volumes were similar, GA = 1,508 cm vs. FTY = 1,489 cm ( = 0.2381). Annualized atrophy rates, adjusted for baseline and at mean baseline value, were GA = -0.2775% vs. FTY = -0.2967% ( = 0.7979). No differences in cognitive measures or PROs were observed. Stable MS patients on long-term treatment with FTY and GA have similar brain volume loss rates. Differences in baseline disease severity may suggest patients with more aggressive disease treated with FTY may achieve similar brain volume loss rates as patients with milder baseline disease on GA.
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http://dx.doi.org/10.3389/fneur.2020.01045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538802PMC
September 2020

Safety results of administering ocrelizumab per a shorter infusion protocol in patients with primary progressive and relapsing multiple sclerosis.

Mult Scler Relat Disord 2020 Nov 18;46:102454. Epub 2020 Aug 18.

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

Background: Ocrelizumab is an approved MS treatment administered as two 300-mg intravenous infusions 2 weeks apart (Dose 1), each lasting approximately 2.5 hours, followed by single 600-mg infusions every 6 months lasting approximately 3.5 hours. Our objective was to evaluate shorter-duration ocrelizumab infusions in the Phase IIIb open-label SaROD study (NCT03606460).

Methods: Eligible patients received ocrelizumab 600-mg Dose 2 or 3 infused over approximately 2 hours (Cohort 1) or ocrelizumab 300-mg Dose 1, Infusion 2 over approximately 1.5 hours (Cohort 2). The primary endpoint was the number and proportion of patients experiencing Grade 3-4 infusion-related reactions (IRRs) in Cohort 1. Secondary endpoints included Grade 1-4 IRRs in both cohorts and Grade 3-4 IRRs in Cohort 2.

Results: Mean infusion times decreased by approximately 1.09 and 0.79 hours in Cohorts 1 and 2, respectively, compared with US prescribing information. IRRs, reported by 36% of 141 patients, were mild-to-moderate, with no observed Grade 3-4 IRRs. No IRR-related discontinuations occurred. No serious AEs, deaths, or new safety signals were observed.

Conclusion: The IRR rate with ocrelizumab shorter-duration infusions was similar to that observed in the pivotal Phase III trials. Ocrelizumab can be infused over a shorter time without sacrificing patient safety.
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http://dx.doi.org/10.1016/j.msard.2020.102454DOI Listing
November 2020

Outcomes of COVID-19 in Patients With Lung Cancer Treated in a Tertiary Hospital in Madrid.

Front Oncol 2020 16;10:1777. Epub 2020 Sep 16.

Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Cancer patients represent a vulnerable population for COVID-19 illness. We aimed to analyze outcomes of lung cancer patients affected by COVID-19 in a tertiary hospital of a high-incidence region during the pandemic. We annotated 23 lung cancer patients consecutively diagnosed with COVID-19 at our institution (HGUGM; Madrid, Spain) between March 4th, 2020 and May 12th, 2020. Only patients with a confirmatory SARS-CoV-2 RT-PCR were included in the study. All patients had at least 1 COVID-19 related symptom; cough (48%), shortness of breath (48%), fever (39%), and low-grade fever (30%) were the most common. Time from symptoms onset to first positive SARS-CoV-2 PCR was 5.5 days (range 1-17), with 13% of cases needed from a 2nd PCR to confirm diagnosis. There was a high variability on thoracic imaging findings, with multilobar pneumonia as the most commonly found pattern (74%). Main lab test abnormalities were low lymphocytes count (87%), high neutrophil to lymphocyte ratio -NLR- (78%), and elevated inflammatory markers: fibrinogen (91%), c-reactive protein -CRP- (87%), and D-dimer (70%). In our series, hospitalization rate was 74%, 39% of patients developed acute respiratory distress syndrome (ARDS), and the case-fatality rate was 35% (8/23). 87% of patients received anti-viral treatment (87% hydroxychloroquine, 74% lopinavir/ritonavir, 13% azithromycin), 43% corticosteroids, 26% interferon-β, 4% tocilizumab, and 82% of hospitalized patients received anticoagulation. High-oxygen requirements were needed in 39% of patients, but only 1 pt was admitted for invasive MV and was discharged 42 days after admission. Multiple variables related to tumor status, clinical baseline conditions, and inflammation markers were associated with mortality but did not remain statistically significant in a multivariate model. In patients with lung cancer receiving systemic therapy ( = 242) incidence and mortality from COVID-19 were 4.5, and 2.1%, respectively, with no differences found by type of treatment. Lung cancer patients represent a vulnerable population for COVID-19, according to the high rate of hospitalization, onset of ARDS, and high mortality rate. Although larger series are needed, no differences in mortality were found by type of cancer treatment. Measures to minimize the risk of SARS-CoV-2 infection remain key to protect lung cancer patients.
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http://dx.doi.org/10.3389/fonc.2020.01777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525070PMC
September 2020

Long-term Follow-up and Optimization of Infliximab in Refractory Uveitis Due to Behçet Disease: National Study of 103 White Patients.

J Rheumatol 2021 May 1;48(5):741-750. Epub 2020 Oct 1.

J.L. Martín-Varillas, MD, B. Atienza-Mateo, MD, V. Calvo-Rio, MD, PhD, R. Demetrio-Pablo, MD, PhD, M.A. González-Gay, MD, PhD, J.L. Hernández, MD, PhD, R. Blanco, MD, PhD, Rheumatology, Internal Medicine and Ophthalmology, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, University of Cantabria.

Objective: In a large series of White patients with refractory uveitis due to Behçet disease (BD) being treated with infliximab (IFX), we assessed (1) long-term efficacy and safety of IFX, and (2) IFX optimization when ocular remission was achieved.

Methods: Our multicenter study of IFX-treated patients with BD uveitis refractory to conventional immunosuppressant agents treated 103 patients/185 affected eyes with IFX as first biologic therapy in the following intervals: 3-5 mg/kg intravenous at 0, 2, 6, and then every 4-8 weeks. The main outcome variables were analyzed at baseline, first week, first month, sixth month, first year, and second year of IFX therapy. After remission, based on a shared decision between patient and clinician, IFX optimization was performed. Efficacy, safety, and cost of IFX therapy were evaluated.

Results: In the whole series (n = 103), main outcome variables showed a rapid and maintained improvement, reaching remission in 78 patients after a mean IFX duration of 31.5 months. Serious adverse events were observed in 9 patients: infusion reactions (n = 4), tuberculosis (n = 1), pneumonia (n = 1), severe oral ulcers (n = 1), palmoplantar psoriasis (n = 1), and colon carcinoma (n = 1). In the optimization subanalysis, the comparative study between optimized and nonoptimized groups showed (1) no differences in clinical characteristics at baseline, (2) similar maintained improvement in most ocular outcomes, (3) lower severe adverse events, and (4) lower mean IFX costs in the optimized group (€4826.52 vs €9854.13 per patient/yr).

Conclusion: IFX seems to be effective and relatively safe in White patients with refractory BD uveitis. IFX optimization is effective, safe, and cost-effective.
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http://dx.doi.org/10.3899/jrheum.200300DOI Listing
May 2021

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells.

Oncoimmunology 2020 06 16;9(1):1773204. Epub 2020 Jun 16.

The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.

The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36CD14PANK allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.
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http://dx.doi.org/10.1080/2162402X.2020.1773204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458638PMC
June 2020

Rituximab versus natalizumab, fingolimod, and dimethyl fumarate in multiple sclerosis treatment.

Ann Clin Transl Neurol 2020 09 6;7(9):1466-1476. Epub 2020 Aug 6.

Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus, University of Colorado, Denver, Colorado.

Introduction: Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist.

Methods: Clinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator.

Results: A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX.

Interpretation: RTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.
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http://dx.doi.org/10.1002/acn3.51111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480919PMC
September 2020

Serious safety events in rituximab-treated multiple sclerosis and related disorders.

Ann Clin Transl Neurol 2020 09 6;7(9):1477-1487. Epub 2020 Aug 6.

NYU Grossman School of Medicine, Department of Neurology, New York University School of Medicine, New York City, New York.

Introduction: Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited.

Methods: Rituximab-treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow-up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician-reported and laboratory data were retrospectively collected from electronic medical records.

Results: One-thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow-up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person-years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair-bound patients had 8.56-fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY.

Interpretation: Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B-cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections.
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http://dx.doi.org/10.1002/acn3.51136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480911PMC
September 2020

Using already-solved cases of a mass disaster event for prioritizing the search among remaining victims: a Bayesian approach.

Sci Rep 2020 03 19;10(1):5026. Epub 2020 Mar 19.

Equipo Argentino de Antropologia Forense, Buenos Aires, Argentina.

This work presents a new method for assisting in the identification process of missing persons in several contexts, such as enforced disappearances. We apply a Bayesian technique to incorporate non-genetic variables in the construction of prior information. In that way, we can learn from the already-solved cases of a particular mass event of death, and use that information to guide the search among remaining victims. This paper describes a particular application to the proposed method to the identification of human remains of the so-called disappeared during the last dictatorship in Argentina, which lasted from 1976 until 1983. Potential applications of the techniques presented hereby, however, are much wider. The central idea of our work is to take advantage of the already-solved cases within a certain event to use the gathered knowledge to assist in the investigation process, enabling the construction of prioritized rankings of victims that could correspond to each certain unidentified human remains.
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http://dx.doi.org/10.1038/s41598-020-59841-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081231PMC
March 2020

Patient-reported outcomes in multiple sclerosis: Validation of the Quality of Life in Neurological Disorders (Neuro-QoL™) short forms.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319885986. Epub 2019 Nov 26.

Department of Neurology, University of Colorado School of Medicine, USA.

Background: Patient-reported outcome (PRO) measures have been shown to be effective for tracking treatment outcomes in multiple sclerosis (MS). However, collecting PROs as part of the clinical standard of care can be time-consuming and examination of their validity for use in an MS sample has been limited.

Objective: To determine the discriminant validity of the Quality of Life in Neurological Disorders (Neuro-QoL™) short forms in a real-world MS clinic population.

Design/methods: Neuro-QoL is a series of questionnaires for tracking physical function, emotional/cognitive health, and social abilities in clinical populations. Neuro-QoL data from 902 MS patients were analyzed for psychometric properties and factor structure.

Results: Neuro-QoL demonstrated acceptable reliability in the moderate-to-good ranges. Moderate support for convergent validity was observed with other measures of MS quality of life, disease severity, and symptoms. However, results from a confirmatory factor analysis suggested poor model fit for most of the 12 domains tested.

Conclusions: These findings support the utility of some of the Neuro-QoL questionnaires in evaluating MS-related PROs. However, additional research may help abridge and strengthen these measures for use in this population.
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http://dx.doi.org/10.1177/2055217319885986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882038PMC
November 2019

Sensory nerve stimulation causes an immediate improvement in motor function of persons with multiple sclerosis: A pilot study.

Mult Scler Relat Disord 2020 Feb 6;38:101508. Epub 2019 Nov 6.

Department of Integrative Physiology, University of Colorado, Boulder, CO, United States.

Background: Multiple sclerosis (MS) symptoms reported in the first year of the disease include sensory impairment, fatigue, reduced mobility, and declines in hand function. The progressive reduction in motor function experienced by persons living with MS is invariably preceded by changes in sensory processing, which are strongly associated with the declines in both walking performance and manual dexterity.

Aims: To assess the influence of concurrent sensory stimulation using augmented transcutaneous electrical nerve stimulation (aTENS) applied to leg and hand muscles on clinical tests of motor function in individuals whose mobility was compromised by MS.

Methods: Thirteen persons with MS (52 ± 8 years; 6 women) and 12 age- and sex-matched healthy adults (52 ± 9 years) met the inclusion criteria. Participants visited the lab on two occasions with one week between visits. Each visit involved the participant performing four tests of motor function and completing two health-related questionnaires (PDDS and MSWS-12). The tests assessed walking performance (6-min test and 25-ft test), dynamic balance (chair-rise tes, and manual dexterity (grooved pegboard test). aTENS was applied through pads attached to the limbs over the tibialis anterior and rectus femoris muscles of the affected leg, and over the median nerve and the thenar eminence of the dominant hand. The pads were attached during both visits, but the current was only applied during the second visit. The stimulation comprised continuous asymmetrical biphasic pulses (0.2 ms) at a rate of 50 Hz and an intensity that elicited slight muscle contractions.

Results: At baseline and during both treatment sessions, the performance on all four tests of motor function was worse for the MS group than the Control group. The MS group experienced significant improvements in all outcomes during the aTENS session with medium-to-large effect sizes. PDDS ratings improved (from 2.8 ± 1.3 to 2.0 ± 1.5; effect size d = -0.70) and the MSWS-12 scores declined (from 36 ± 11 to 28 ± 12; effect size d = -1.52). The concurrent application of aTENS enabled the MS group to walk further during the 6-min test (from 397 ± 174 m to 415 ± 172 m; effect size d = 0.81), to complete the 25-ft test in less time (6.7 ± 3.0 s to 6.3 ± 2.9 s; effect size d = -0.76), to increase the counts in the chair-rise test (from 11.2 ± 3.8 to 13.6 ± 4.8; effect size d = 1.52), and to perform the grooved pegboard test more quickly (from 110 ± 43 s to 99 ± 37 s; effect size d = -0.98). The only significant effect for the Control group was a significant increase in the 6-min walk distance (from 725 ± 79 to 740 ± 82 m; effect size d = 0.87).

Conclusions: Stimulation of sensory fibers with aTENS evoked clinically significant improvements in four tests of motor function and the self-reported level of walking limitations in persons who were moderately disabled by MS. Moreover, the improvements in function elicited by the concurrent application of aTENS were immediate.
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http://dx.doi.org/10.1016/j.msard.2019.101508DOI Listing
February 2020

A Novel Tool to Improve Shared Decision Making and Adherence in Multiple Sclerosis: Development and Preliminary Testing.

MDM Policy Pract 2019 Jul-Dec;4(2):2381468319879134. Epub 2019 Oct 16.

University of Massachusetts Medical School, Worchester, Massachusetts.

. Most people with multiple sclerosis (MS) want to be involved in medical decision making about disease-modifying therapies (DMTs), but new approaches are needed to overcome barriers to participation. . We sought to develop a shared decision-making (SDM) tool for MS DMTs, evaluate patient and provider responses to the tool, and address challenges encountered during development to guide a future trial. . We created a patient-centered design process informed by image theory to develop the MS-SUPPORT SDM tool. Development included semistructured interviews and alpha and beta testing with MS patients and providers. Beta testing assessed dissemination and clinical integration strategies, decision-making processes, communication, and adherence. Patients evaluated the tool before and after a clinic visit. . MS-SUPPORT combines self-assessment with tailored feedback to help patients identify their treatment goals and preferences, correct misperceptions, frame decisions, and promote adherence. MS-SUPPORT generates a personal summary of their responses that patients can share with their provider to facilitate communication. Alpha testing (14 patients) identified areas needing improvement, resulting in reorganization and shortening of the tool. MS-SUPPORT was highly rated in beta testing (15 patients, 4 providers) on patient-provider communication, patient preparation, adherence, and other endpoints. Dissemination through both patient and provider networks appeared feasible. All patient testers wanted to share the summary report with their provider, but only 60% did. . Small sample size, no comparison group. . The development process resulted in a patient-centered SDM tool for MS that may facilitate patient involvement in decision making, help providers understand their patients' preferences, and improve adherence, though further testing is needed. Beta testing in real-world conditions was critical to prepare the tool for future testing and inform the design of future studies.
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http://dx.doi.org/10.1177/2381468319879134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798166PMC
October 2019

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

Rituximab-induced serum sickness in multiple sclerosis patients.

Mult Scler Relat Disord 2019 Nov 17;36:101402. Epub 2019 Sep 17.

Department of Neurology, University of Colorado School of Medicine, 12631 East 17th Avenue, Aurora, CO 80045 USA; Rocky Mountain Multiple Sclerosis Center, 12631 East 17th Avenue, Aurora, CO 80045 USA. Electronic address:

Rituximab is a chimeric anti-CD20 monoclonal antibody that is an effective therapy for multiple sclerosis. Rituximab has been associated with the development of serum sickness (type III hypersensitivity) characterized by arthralgia, fever, and rash during the treatment of other conditions, such as rheumatoid arthritis. Here we describe serum sickness associated with rituximab in multiple sclerosis patients and discuss both the management of serum sickness itself and implications for utilizing alternative anti-CD20 monoclonal antibodies for disease management in this patient population.
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http://dx.doi.org/10.1016/j.msard.2019.101402DOI Listing
November 2019

CNS atypical T-cell lymphoproliferative disease following treatment with alemtuzumab.

Neurol Clin Pract 2019 Jun;9(3):273-276

Department of Neurology (MK, DEN, BKK-D, LH, EA, ALP), Department of Neurosurgery (DEN, BKK-D), and Department of Pathology (BKK-D), University of Colorado, Aurora, CO.

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http://dx.doi.org/10.1212/CPJ.0000000000000639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615657PMC
June 2019

Comparative Study of Infliximab Versus Adalimumab in Refractory Uveitis due to Behçet's Disease: National Multicenter Study of 177 Cases.

Arthritis Rheumatol 2019 12 21;71(12):2081-2089. Epub 2019 Oct 21.

Hospital de Pontevedra, Pontevedra, Spain.

Objective: To compare the efficacy of infliximab (IFX) versus adalimumab (ADA) as a first-line biologic drug over 1 year of treatment in a large series of patients with refractory uveitis due to Behçet's disease (BD).

Methods: We conducted an open-label multicenter study of IFX versus ADA for BD-related uveitis refractory to conventional nonbiologic treatment. IFX or ADA was chosen as the first-line biologic agent based on physician and patient agreement. Patients received 3-5 mg/kg intravenous IFX at 0, 2, and 6 weeks and every 4-8 weeks thereafter, or 40 mg subcutaneous ADA every other week without a loading dose. Ocular parameters were compared between the 2 groups.

Results: The study included 177 patients (316 affected eyes), of whom 103 received IFX and 74 received ADA. There were no significant baseline differences between treatment groups in main demographic features, previous therapy, or ocular sign severity. After 1 year of therapy, we observed an improvement in all ocular parameters in both groups. However, patients receiving ADA had significantly better outcomes in some parameters, including improvement in anterior chamber inflammation (92.31% versus 78.18% for IFX; P = 0.06), improvement in vitritis (93.33% versus 78.95% for IFX; P = 0.04), and best-corrected visual acuity (mean ± SD 0.81 ± 0.26 versus 0.67 ± 0.34 for IFX; P = 0.001). A nonsignificant difference was seen for macular thickness (mean ± SD 250.62 ± 36.85 for ADA versus 264.89 ± 59.74 for IFX; P = 0.15), and improvement in retinal vasculitis was similar between the 2 groups (95% for ADA versus 97% for IFX; P = 0.28). The drug retention rate was higher in the ADA group (95.24% versus 84.95% for IFX; P = 0.042).

Conclusion: Although both IFX and ADA are efficacious in refractory BD-related uveitis, ADA appears to be associated with better outcomes than IFX after 1 year of follow-up.
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http://dx.doi.org/10.1002/art.41026DOI Listing
December 2019

B cell depletion with ublituximab reshapes the T cell profile in multiple sclerosis patients.

J Neuroimmunol 2019 07 3;332:187-197. Epub 2019 May 3.

Central Texas Neurology Consultants, UT Dell Medical School, Austin, TX, USA.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, thought to be mediated by myelin-specific CD4+ T cells. However, B cell depletion has proven to be an effective therapy for MS, but the mechanism is not well understood. This study was designed to determine how B cell depletion changes lymphocyte profiles. During a phase IIa clinical trial with ublituximab, a novel CD20 antibody, blood was collected from 48 MS patients at 11 time points over 24 weeks and the lymphocyte profiles were analyzed by flow cytometry. The percentage of naïve CD4+ and CD8+ T cells increased, while the percentage of both effector and central memory T cells declined. CD4+ Th1 effector cells decreased, while there was a significant increase in CD4+ regulatory T cells. The depletion of B cells had a favorable shift in the lymphocyte landscape, reducing the number of naïve T cells becoming activated and transitioning to memory T cells. The ratio of Th1 cells to CD4+ regulatory T cells declined, suggesting that immune regulation was being restored. These data suggest that loss of B cells as antigen presenting cells is a major mechanism of action for the beneficial effects of CD20 antibody therapy in MS.
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http://dx.doi.org/10.1016/j.jneuroim.2019.04.017DOI Listing
July 2019

Monoclonal Antibodies in Multiple Sclerosis: Present and Future.

Biomedicines 2019 Mar 14;7(1). Epub 2019 Mar 14.

Rocky Mountain Multiple Sclerosis Center at the University of Colorado, Department of Neurology, University of Colorado School of Medicine, Academic Office 1, Mail Stop B-185, 12631 East 17th Avenue, Aurora, CO 80045, USA.

The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future.
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http://dx.doi.org/10.3390/biomedicines7010020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466331PMC
March 2019

Natalizumab versus fingolimod and dimethyl fumarate in multiple sclerosis treatment.

Ann Clin Transl Neurol 2019 02 9;6(2):252-262. Epub 2018 Dec 9.

Division of Neuroimmunology Department of Neurology Rocky Mountain Multiple Sclerosis Center at the University of Colorado Aurora Colorado.

Objective: To compare 2-year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS).

Methods: Patients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician-reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator.

Results: A total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11-12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41-2.85],  < 0.001) and 2.38 [95% CI: 1.68-3.37],  < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse. At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively. The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%).

Interpretation: NTZ appears to be more effective and tolerable than FTY and DMF.
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http://dx.doi.org/10.1002/acn3.700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389745PMC
February 2019

Subjective cognitive concern in multiple sclerosis is associated with reduced thalamic and cortical gray matter volumes.

Mult Scler J Exp Transl Clin 2019 Jan-Mar;5(1):2055217319827618. Epub 2019 Feb 13.

Department of Psychology, University of Houston, USA.

Objective: Brain atrophy has been correlated with objective cognitive dysfunction in multiple sclerosis but few studies have explored self-reported subjective cognitive concerns and their relationship to brain volume changes. This study explores the relationship between subjective cognitive concerns in multiple sclerosis and reduced brain volume in regions of interest implicated in cognitive dysfunction.

Methods: A total of 158 patients with multiple sclerosis completed the Quality of Life in Neurologic Disorders Measures (Neuro-QoL) short forms to assess subjective cognitive concerns and underwent brain magnetic resonance imaging. Regional brain volumes from regions of interest implicated in cognitive dysfunction were measured using NeuroQuant automated volumetric quantitation. Linear regression was used to analyze the relationship between subjective cognitive concerns and brain volume.

Results: Controlling for age, disease duration, gender, depression and fatigue, increased subjective cognitive concerns were associated with reduced thalamic volume (standardized  = 0.223, t =2.406,  = 0.017) and reduced cortical gray matter volume (standardized  = 0.240, t = 2.777,  = 0.006). Increased subjective cognitive concerns were not associated with any other regions of interest that were analyzed.

Conclusions: Subjective cognitive concern in MS is associated with reduced thalamic and cortical gray matter volumes, areas of the brain that have been implicated in objective cognitive impairment. These findings may lend neuroanatomical significance to subjective cognitive concerns and patient-reported outcomes as measured by Neuro-QoL.
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http://dx.doi.org/10.1177/2055217319827618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378429PMC
February 2019

Real-World Characterization of Dimethyl Fumarate-Related Gastrointestinal Events in Multiple Sclerosis: Management Strategies to Improve Persistence on Treatment and Patient Outcomes.

Neurol Ther 2019 Jun 31;8(1):109-119. Epub 2019 Jan 31.

Department of Neurology, Inselspital-Bern University Hospital, University of Bern, Bern, Switzerland.

Introduction: Delayed-release dimethyl fumarate (DMF) is an effective treatment for multiple sclerosis (MS). Some patients experience gastrointestinal (GI) adverse events (AEs) that may lead to premature DMF discontinuation. This study characterized the impact of site-specific GI management strategies on the occurrence of GI events and discontinuation patterns.

Methods: Data on GI events and DMF persistence were retrospectively abstracted from medical records of patients treated with DMF in routine medical practice in the EFFECT study (NCT02776072). GI management strategies were assessed via a study site questionnaire. Discontinuation rates were analyzed according to counseling patterns.

Results: Of 826 DMF-treated patients at 66 sites, 809 from 65 sites were eligible for the GI analysis; of these, 27% experienced GI AEs. Within 1 year of treatment, 14% (118/826) of patients discontinued DMF, 5% (44/809) due to GI events. Most sites (92%) reported that patients were very likely (> 75% of the time) to be counseled about GI events at/before DMF treatment initiation and/or to be recommended that DMF be taken with food (86%); 48% of sites reported to be very likely to recommend using symptomatic therapies for GI AEs. Lower discontinuation rates were reported at sites very likely versus not very likely (≤ 75% of the time) to (1) provide counseling; (2) provide specific details regarding GI events; or (3) recommend taking DMF with food, and/or using symptomatic GI therapies.

Conclusion: Counseling and other GI management strategies at initiation of DMF treatment appear to reduce the burden of GI events, and a variety of GI management strategies may improve DMF persistence.

Trial Registration: NCT02776072.

Funding: Biogen (Cambridge, MA, USA).
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http://dx.doi.org/10.1007/s40120-019-0127-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534646PMC
June 2019

Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis.

Neurology 2019 02 11;92(7):e723-e732. Epub 2019 Jan 11.

From the Departments of Radiology (J.M.H.) and Clinical Pharmacy (K.V.N.), University of Colorado Hospital, Aurora; Department of Neurology (K.V.N., S.S., B.V., E.A., T.S., J.R.C., T.L.V.), University of Colorado, and Rocky Mountain Multiple Sclerosis Center at the University of Colorado, Aurora; and Department of Neurology (A.M.), University of Florida, Gainesville. Dr. Miravalle is currently at Advanced Neurology of Colorado, Fort Collins, Colorado.

Objective: To examine whether rituximab induction followed by glatiramer acetate (GA) monotherapy is more effective than GA alone for the treatment of relapsing multiple sclerosis with active disease.

Methods: This was a single-center, double-blind, placebo-controlled study. Fifty-five participants were randomly assigned (1:1 ratio) to either rituximab (R-GA) or placebo (P-GA) induction, followed by GA therapy initiated in all participants. Participants were followed up to 3 years. The primary endpoint was the number of participants with no evidence of disease activity (NEDA): those without relapse, new MRI lesions, and sustained change in disability.

Results: Twenty-eight and 27 participants received rituximab and placebo induction, respectively, with one participant in each arm withdrawing before 6-month MRI. There were no significant differences in baseline characteristics. At end of study, 44.44% of R-GA participants demonstrated NEDA vs 19.23% of P-GA participants ( = 0.049). Treatment failed for a smaller proportion of R-GA participants (37.04% R-GA vs 69.23% P-GA, = 0.019), and time to treatment failure was longer (23.32 months R-GA vs 11.29 months P-GA, = 0.027). Fewer participants in the R-GA arm had new lesions (25.93% R-GA vs 61.54% P-GA, = 0.009), and there were fewer new T2 lesions (0.48 R-GA vs 1.96 P-GA, = 0.027). Probability of demonstrating NEDA in the R-GA arm returned to baseline within the study period. There were no differences in adverse events.

Conclusions: Induction therapy with rituximab followed by GA may provide superior efficacy in the short term than GA alone in relapsing multiple sclerosis, but this benefit appears to wane within the study period. Larger studies are needed to assess sustainability of results.

Clinicaltrialsgov Identifier: NCT01569451.
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http://dx.doi.org/10.1212/WNL.0000000000006916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382366PMC
February 2019

Evaluation of a Novel Preference Assessment Tool for Patients with Multiple Sclerosis.

Int J MS Care 2018 Nov-Dec;20(6):260-267

Background: We developed a preference assessment tool to help assess patient goals, values, and preferences for multiple sclerosis (MS) management. All preference items in the tool were generated by people with MS. The aim of this study was to evaluate this tool in a national sample of people with MS.

Methods: English-speaking patients with MS aged 21 to 75 years with access to the internet were recruited. Participants completed the preference tool online, which included separate modules assessing three core preference areas: treatment goals, preferences for attributes of disease-modifying therapies, and factors influencing a change in treatment. The tool generated a summary of participants' treatment goals and preferences. Immediately after viewing the summary, participants were asked to evaluate the tool. Rankings of preference domains were compared with rankings obtained in another study.

Results: In 135 people with MS who completed the tool and evaluation, the highest ranked goal was brain health (memory, thinking, brain), followed by disability concerns (walking, strength, vision). Rankings were highly similar to those in the referent study. Nearly all participants reported that the tool helped them understand their goals and priorities regarding MS and that the summary appropriately reflected what is important to them. Most participants (87%) wanted to discuss their treatment goals and priorities with their clinician.

Conclusions: This preference assessment tool successfully captured patients' goals, values, and preferences for MS treatment and could potentially be used to help patients communicate their preferences to their clinician.
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http://dx.doi.org/10.7224/1537-2073.2017-021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295881PMC
December 2018

Exploring cannabis use by patients with multiple sclerosis in a state where cannabis is legal.

Mult Scler Relat Disord 2019 Jan 20;27:383-390. Epub 2018 Nov 20.

Department of Neurology, University of Colorado School of Medicine, 12700 East 19th Ave, B182, Aurora, CO 80045, United States. Electronic address:

Background: Studies suggest cannabis may improve symptoms like pain and muscle spasticity in patients with multiple sclerosis (PwMS). Despite cannabis' new-found legality and availability, few studies have explored the profile of PwMS cannabis users and characteristics of their use, particularly in a state where cannabis is legal both for recreational and medicinal use. The purpose of the current study was to evaluate cannabis use among PwMS at a large academic multiple sclerosis (MS) clinic, specifically: (1) prevalence, (2) products used (e.g., cannabidiol vs Δ-tetrahydocannabinol), (3) symptom treatment, and (4) patient characteristics.

Methods: PwMS completed questions assessing personal opinions about cannabis use, characteristics of cannabis use, MS history, and sociodemographic details, as well as the self-reported disability-Patient Determined Disease Steps (PDDS), overall quality of life-the Patient Reported Outcome Measure Information System (PROMIS-10), and cognition-the Neuro-QoL ACGC v1.0 measures.

Results: Thirty-eight percent (n = 96) of PwMS were current Cannabis users (CUs). Although there were no sociodemographic or clinical differences (p ≤ 0.05) between CUs and Non-Cannabis users (NUs), CUs had significantly higher median disability compared to NUs (PDDS = 2 vs. 1; p = 0.02). Among CUs, 57% categorized their use as strictly medicinal. CUs reported using cannabis most often for pain and insomnia/poor sleep and experienced greater than 60% benefit/relief from cannabis use. Over 90% of respondents desire more research on cannabis for MS, and 74% indicated they would consider using cannabis for their MS.

Conclusion: As cannabis legalization has impacted the variety of cannabis products available, there appears to be growing numbers of PwMS using cannabis, with this study's CUs reporting use of highly efficacious products with minimal side-effects.
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http://dx.doi.org/10.1016/j.msard.2018.11.022DOI Listing
January 2019

We need to conduct clinical trials of disease-modifying therapy in pregnancy to optimize care of women with MS - Yes.

Mult Scler 2019 02 22;25(2):187-188. Epub 2018 Oct 22.

Departments of Neurology and Epidemiology, Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1177/1352458518794061DOI Listing
February 2019

Impact of fingolimod on clinical and magnetic resonance imaging outcomes in routine clinical practice: A retrospective analysis of the multiple sclerosis, clinical and MRI outcomes in the USA (MS-MRIUS) study.

Mult Scler Relat Disord 2019 Jan 3;27:65-73. Epub 2018 Oct 3.

Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, NY, USA. Electronic address:

Background: The effectiveness of fingolimod on clinical and magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis (MS) has been well established in trials and, to a lesser extent, in the real world.

Objective: To evaluate clinical and MRI outcomes in patients with relapsing MS receiving fingolimod in US clinical practice.

Methods: Clinical and MRI data from 590 patients initiating fingolimod treatment at 33 MS centers in the USA were retrospectively analyzed. Clinical data were obtained from medical records. MRI data were systematically quantified at a centralized imaging facility. Patients had an index (within 6 months before and 1 month after starting fingolimod) and post-index (9-24 months after starting fingolimod) MRI scan; 184 individuals had a pre-index scan (9-24 months before starting fingolimod).

Results: In the index to post-index period, mean annualized relapse rates decreased from 0.36 to 0.13 and disability progression occurred in 18.5% of patients. Median T2, T1 and gadolinium-enhancing lesion volume changed by 1.15%, 2.36%, and -100% between the index and post-index scans, respectively, and median annualized percentage changes in brain volume and lateral ventricular volume were -0.32% and +0.66%, respectively. For patients with pre-index scans, MRI outcomes were unchanged or improved during treatment. Outcomes were generally comparable with those in fingolimod phase 3 trials.

Conclusion: This real-world study highlights the effectiveness of fingolimod and the feasibility of quantifying clinical and MRI data collected from multiple centers during routine clinical practice on a group level using a systematic, quantitative methodology.
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http://dx.doi.org/10.1016/j.msard.2018.09.037DOI Listing
January 2019

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

N Engl J Med 2018 08;379(9):846-855

From the Mellen Center for Multiple Sclerosis, Neurological Institute (R.J.F., S. Natarajan, R.A.B., D.O.), the Imaging Institute (X.H., M.J.L., K.E.S., X.Z.), and the Department of Biomedical Engineering (P.J., K.N., B. Thoomukuntla), Cleveland Clinic, Cleveland, Ohio State University, Columbus (M.R.), and University of Cincinnati, Cincinnati (A.Z.) - all in Ohio; the Data Coordinating Center, Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), University of Iowa, Iowa City (C.S.C., J.B., D.E., E.K., M.K., J.D.L., J.Y.); the National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); the Clinical Coordinating Center, NeuroNEXT, Massachusetts General Hospital, Neurological Clinical Research Institute, Harvard Partners (M.E.C., M.M., A.A., B. Thornell), the Department of Neurology, Massachusetts General Hospital, Harvard Medical School (E.C.K.), and Brigham and Women's Hospital (C.S.), Boston; patient advocate (T.G.) and Swedish Medical Center at Seattle (P.R.), Seattle; University of Rochester Medical Center, Rochester (A.G.), Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center (S.K.), Weill Cornell Medical College (J.S.P.), Columbia University Medical Center (C.S.R.), and Montefiore Medical Center, Albert Einstein College of Medicine (S.S.), New York, State University of New York (SUNY) at Stony Brook, Stony Brook (P.K.C.), SUNY Upstate Medical University, Syracuse (B.J.), and SUNY at Buffalo, Buffalo (B.W.-G.) - all in New York; MediciNova, La Jolla (K.M.), University of California at Davis, Sacramento (M.A.), and University of California at Los Angeles, Los Angeles (B.S.G.) - all in California; Washington University School of Medicine, St. Louis (R.T.N.); Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (J.P.D.); NeuroRx Research, Montreal (S. Narayanan); the School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN (X.Z.); University of Colorado Denver, Aurora (E.A.); University of Alabama at Birmingham, Birmingham (K.B.); Feinberg School of Medicine, Northwestern University, Chicago (B.A.C.); University of Miami Miller School of Medicine, Miami (S.D.); University of Utah, Salt Lake City (L.D.D.); University of Texas Southwestern Medical Center, Dallas (A.F.); University of Virginia at Charlottesville, Charlottesville (M.D.G.); Emory University, Atlanta (N.L.); University of Kansas Medical Center, Kansas City (S.G.L.); Vanderbilt University, Nashville (H.M.); University of Pittsburgh Medical Center, Pittsburgh (V.S.); and Oregon Health and Science University, Portland (V.Y.).

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 .).
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http://dx.doi.org/10.1056/NEJMoa1803583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172944PMC
August 2018