Publications by authors named "Robert Fox"

386 Publications

Seeking progress in disease modification in Parkinson disease.

Parkinsonism Relat Disord 2021 Sep 10. Epub 2021 Sep 10.

The Cure Parkinson's Trust, London, UK.

Objective: Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions.

Methods: The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD.

Results: Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders.

Conclusions: We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.006DOI Listing
September 2021

Relationship Between Serum Neurofilament Light and Multiple Sclerosis Disability Progression: Clear as Mud.

Neurology 2021 Sep 9. Epub 2021 Sep 9.

Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

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http://dx.doi.org/10.1212/WNL.0000000000012755DOI Listing
September 2021

Patient Perceptions of FDA Approval: Gaps in Education or Variation in Values?

Neurol Clin Pract 2021 Aug;11(4):273-279

Neuroethics Program (PJF), Cleveland Clinic; Mellen Center for Multiple Sclerosis (RJF), Cleveland Clinic; Department of Bioethics (MBM), Cleveland Clinic, OH; and Department of Biostatistics (SSC), The University of Alabama at Birmingham.

Objective: To assess perceptions and opinions about the Food and Drug Administration (FDA) approval process for disease-modifying therapies (DMT) in people living with multiple sclerosis (MS).

Methods: People living with MS were invited to complete a web-based survey of their perceptions of the FDA role and process for approval of MS medications. The survey asked about the role of the FDA, factors involved in the approval process, which voices should represent those with MS in deliberations about drug approval, and the level of comfort with uncertain safety of newly approved therapies.

Results: Three thousand thirty-three respondents met inclusion criteria for data analysis. Most respondents seemed to understand the role of the FDA, although only half understood a fundamental FDA role: balancing the risks and benefits when considering drug approval. Significant differences were observed in many areas between those who have and have not tried DMTs. Comfort with uncertainty was associated with several factors relating to side effects and benefits believed important for the FDA to consider. Most respondents reported that people who participated in the medication's clinical trial were particularly able to represent people living with MS.

Conclusion: Perceptions regarding the FDA and views of who should represent people living with MS varied between those who have and have not tried DMT. There is variability in personal values that should be recognized and taken into account when considering regulatory responsibilities. Interventions are needed to address educational gaps regarding the mission and trustworthiness of the FDA as an oversight body.
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http://dx.doi.org/10.1212/CPJ.0000000000001034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382396PMC
August 2021

Uptake and Attitudes About Immunizations in People With Multiple Sclerosis.

Neurol Clin Pract 2021 Aug;11(4):327-334

Departments of Internal Medicine and Community Health Sciences (RAM), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Family Medicine Max Rady College of Medicine (LK), Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Biostatistics (GRC), University of Alabama at Birmingham, AL; Mellen Center for Multiple Sclerosis (RF), Neurological Institute, Cleveland Clinic, OH; and Department of Biostatistics (AS), Washington University in St. Louis, MO.

Objective: By surveying a multiple sclerosis (MS) population, we tested the hypothesis that influenza vaccine uptake would not meet public health targets and that vaccine misconceptions would contribute to lower than desired uptake.

Methods: In spring 2020, we surveyed participants in the North American Research Committee on Multiple Sclerosis Registry regarding vaccinations. Participants reported whether they had received hepatitis A, hepatitis B, pneumococcal, shingles, varicella, measles/mumps/rubella, tetanus, or influenza vaccines. Participants who had not received influenza vaccine last year reported the reasons. We summarized responses descriptively. Using multivariable logistic regression, we assessed participant characteristics associated with uptake of seasonal influenza vaccine.

Results: Of 5,244 eligible respondents, 80.8% were female, with a mean (SD) age of 61.8 (10.1) years. Overall, 43.0% (2,161/5,032) of participants reported that their neurologist had ever asked about their immunization history. The percentage of participants who received the seasonal flu vaccine last year ranged from 59.1% among those aged 18-24 years to 79.9% for persons aged ≥65 years. Among those who did not get the influenza vaccination, the most common reasons were personal preference (29.6%), concerns about possible adverse effects in general (29.3%), and concerns that the vaccine would worsen their MS (23.7%).

Conclusion: Vaccination uptake is lower than desired in the MS population compared with existing recommendations, including for seasonal influenza. Misconceptions about the safety of vaccination in the context of MS and personal preference appear to play important roles in vaccination choices, highlighting the importance of education about these issues.
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http://dx.doi.org/10.1212/CPJ.0000000000001099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382432PMC
August 2021

Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results.

Mult Scler 2021 Sep 1:13524585211037909. Epub 2021 Sep 1.

Biogen, Cambridge, MA, USA.

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit-risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension.

Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE.

Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0-2), then DMF (Years 3-10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years.

Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04-10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF ( = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120-0.169)), while for PBO/DMF ( = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0-2 years, 0.330 (95% CI, 0.266-0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118-0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening.

Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment.
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http://dx.doi.org/10.1177/13524585211037909DOI Listing
September 2021

COVID-19 in Patients With Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody Disease in North America: From the COViMS Registry.

Neurol Neuroimmunol Neuroinflamm 2021 09 24;8(5). Epub 2021 Aug 24.

From the Johns Hopkins University School of Medicine (S.D.N.), Baltimore, MD; Washington University in St. Louis School of Medicine (A.H.C., A.S.), MO; Mellen Center for MS (R.J.F.), Cleveland Clinic, OH; Consortium of MS Centers (J.H.), Hackensack, NJ; MS Society of Canada (P.K.), Toronto, Ontario, Canada; National Multiple Sclerosis Society (B.B.) New York, NY; University of British Columbia (D.L.), Vancouver, British Columbia, Canada; The University of Alabama at Birmingham (G.R.C.); and University of Miami School of Medicine (K.W.R.), FL.

Background And Objective: To describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

Methods: The COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using -tests, Pearson χ tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity.

Results: As of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%-75.5%]), whereas 15.6% (95% CI: 8.3%-25.6%) were hospitalized only, 9.1% (95% CI: 3.7%-17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%-19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79-19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated.

Discussion: Among the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size.
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http://dx.doi.org/10.1212/NXI.0000000000001057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407145PMC
September 2021

Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.

Lancet Neurol 2021 09;20(9):729-738

Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

Background: Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis.

Methods: We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed.

Findings: Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred.

Interpretation: 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis.

Funding: Sanofi.
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http://dx.doi.org/10.1016/S1474-4422(21)00237-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434816PMC
September 2021

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren's Syndrome: Clues for a Personalized Medicine.

Front Immunol 2021 12;12:703780. Epub 2021 Jul 12.

Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, CA, United States.

Common variable immunodeficiency disorders (CVID) are a group of rare diseases of the immune system and the most common symptomatic primary antibody deficiency in adults. The "variable" aspect of CVID refers to the approximately half of the patients who develop non-infective complications, mainly autoimmune features, in particular organ specific autoimmune diseases including thyroiditis, and cytopenias. Among these associated conditions, the incidence of lymphoma, including mucosal associated lymphoid tissue (MALT) type, is increased. Although these associated autoimmune disorders in CVID are generally attributed to Systemic Lupus Erythematosus (SLE), we propose that Sjogren's syndrome (SS) is perhaps a better candidate for the associated disease. SS is an autoimmune disorder characterized by the lymphocytic infiltrates of lacrimal and salivary glands, leading to dryness of the eyes and mouth. Thus, it is a lymphocyte aggressive disorder, in contrast to SLE where pathology is generally attributed to auto-antibody and complement activation. Although systemic lupus erythematosus (SLE) shares these features with SS, a much higher frequency of MALT lymphoma distinguishes SS from SLE. Also, the higher frequency of germ line encoded paraproteins such as the monoclonal rheumatoid factor found in SS patients would be more consistent with the failure of B-cell VDJ switching found in CVID; and in contrast to the hypermutation that characterizes SLE autoantibodies. Thus, we suggest that SS may fit as a better "autoimmune" association with CVID. Examining the common underlying biologic mechanisms that promote lymphoid infiltration by dysregulated lymphocytes and lymphoma in CVID may provide new avenues for treatment in both the diseases. Since the diagnosis of SLE or rheumatoid arthritis is usually based on specific autoantibodies, the associated autoimmune features of CVID patients may not be recognized in the absence of autoantibodies.
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http://dx.doi.org/10.3389/fimmu.2021.703780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311857PMC
July 2021

Posttraumatic stress disorder, complex PTSD and subtypes of loneliness among older adults.

J Clin Psychol 2021 Jul 20. Epub 2021 Jul 20.

Department of Psychology, Maynooth University, Kildare, Ireland.

Objectives: Research examining the relationship between loneliness and Complex Posttraumatic Stress Disorder (CPTSD) is scarce, particularly among older adults. CPTSD includes the core symptoms of PTSD along with additional symptoms reflecting "disturbances in self-organisation" (DSO). This study examined the cross-sectional relationships between loneliness (emotional and social loneliness) and CPTSD symptoms (i.e., PTSD and DSO symptoms) in older adults.

Methods: Structural equation modelling was used to examine these relationships in a nationally representative sample of US adults aged 60-70 years (n = 456).

Results: Controlling for covariates, emotional loneliness was associated with PTSD (β = 0.31) and DSO (β = 0.57) symptoms whereas social loneliness was only associated with DSO symptoms (β = 0.25). The model explained 35.0% of the variance in PTSD symptoms and 71.3% in DSO symptoms.

Conclusion: These findings have important implications for treating and understanding PTSD/CPTSD and their correlates among older adults.
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http://dx.doi.org/10.1002/jclp.23225DOI Listing
July 2021

Posttraumatic stress disorder, complex PTSD and subtypes of loneliness among older adults.

J Clin Psychol 2021 Jul 20. Epub 2021 Jul 20.

Department of Psychology, Maynooth University, Kildare, Ireland.

Objectives: Research examining the relationship between loneliness and Complex Posttraumatic Stress Disorder (CPTSD) is scarce, particularly among older adults. CPTSD includes the core symptoms of PTSD along with additional symptoms reflecting "disturbances in self-organisation" (DSO). This study examined the cross-sectional relationships between loneliness (emotional and social loneliness) and CPTSD symptoms (i.e., PTSD and DSO symptoms) in older adults.

Methods: Structural equation modelling was used to examine these relationships in a nationally representative sample of US adults aged 60-70 years (n = 456).

Results: Controlling for covariates, emotional loneliness was associated with PTSD (β = 0.31) and DSO (β = 0.57) symptoms whereas social loneliness was only associated with DSO symptoms (β = 0.25). The model explained 35.0% of the variance in PTSD symptoms and 71.3% in DSO symptoms.

Conclusion: These findings have important implications for treating and understanding PTSD/CPTSD and their correlates among older adults.
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http://dx.doi.org/10.1002/jclp.23225DOI Listing
July 2021

Secondary Progressive Multiple Sclerosis: New Insights.

Neurology 2021 08 4;97(8):378-388. Epub 2021 Jun 4.

From the UCSF Weill Institute for Neurosciences, Department of Neurology (B.A.C.C.), University of California San Francisco; NeuroRx Research (D.L.A.), Montreal; Brain Imaging Centre (D.L.A.), Montreal Neurological Institute, McGill University, Canada; Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation (J.C.), UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London; National Institute for Health Research (J.C.), University College London Hospitals, Biomedical Research Centre, UK; Brigham Multiple Sclerosis Center (T.C.), Brigham and Women's Hospital, Boston, MA; Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute (R.J.F.), Cleveland Clinic, OH; Oxford PharmaGenesis (A.P.R.), UK; Novartis Pharma AG (N.M.), Basel, Switzerland; and Center for Brain Research (H.L.), Medical University of Vienna, Austria.

In most cases, multiple sclerosis (MS) begins with a relapsing-remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive MS (SMPS). Major differences exist between relapsing-remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment. This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS. We emphasize the criticality of conversion from a relapsing-remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS. Clear clinical, imaging, immunologic, or pathologic criteria marking the transition from RRMS to SPMS have not yet been established. Early identification of SPMS will require tools that, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.
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http://dx.doi.org/10.1212/WNL.0000000000012323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397587PMC
August 2021

A mixed methods protocol to evaluate the effectiveness and acceptability of COVID-19 Community Assessment Hubs.

HRB Open Res 2021 12;4:16. Epub 2021 May 12.

Centre for Interdisciplinary Research Education and Innovation in Health Systems (IRIS), School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, D04 V1W8, Ireland.

Ireland's health system has been under significant strain due to staff shortages and inadequate capacity. Critical care bed capacity per capita in Ireland is among the lowest in Europe, thus, the coronavirus disease 2019 (COVID-19) pandemic has put additional strain on an over-stretched system. COVID-19 Community Assessment Hubs (CAHs) were established to mitigate unnecessary admission to acute hospitals, and reduce infection spread by supporting COVID-19 positive or suspected positive patients to isolate at home, or in isolation facilities. There is some evidence that similar assessment centres may be a successful triage strategy to reduce burden on hospital and acute care. The aim of this study is to evaluate the impact of COVID-19 Community Assessment Hubs on service delivery in two regions in Ireland during the pandemic. A mixed-methods approach will be used, incorporating co-design to engage stakeholders and ensure informed data capture and analysis. Online surveys will assess CAH patients' experiences of access to and quality of care. Clinical patient data from CAHs will be collected and analysed using multinomial logistic regression to check for association with patient demographics and COVID-19 symptoms, and CAH early warning scores and outcomes (Transfer to Emergency Department, Transfer to isolation unit, Sent home with care plan). Semi-structured interviews will be conducted with: patients to elicit an in-depth understanding of experiences and acceptability of attending CAHs; and staff to understand challenges, benefits, and effectiveness of CAHs. Interview data will be analysed using thematic analysis. : This study will provide valuable insights from both patient and staff perspectives on the operation of CAHs. We will evaluate the effectiveness and acceptability of CAHs and propose areas for improvement of the service. This will contribute to international literature on the use of community assessment centres during infectious disease pandemics.
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http://dx.doi.org/10.12688/hrbopenres.13217.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136252PMC
May 2021

Influence of equipment changes on MRI measures of brain atrophy and brain microstructure in a placebo-controlled trial of ibudilast in progressive multiple sclerosis.

Mult Scler J Exp Transl Clin 2021 Apr-Jun;7(2):20552173211010843. Epub 2021 May 18.

Mellen Center for Multiple Sclerosis, Neurological Institute, The Cleveland Clinic, Cleveland, OH, USA.

Background: Hardware changes can be an unavoidable confound in imaging trials. Understanding the impact of such changes may play an important role in the analysis of imaging data.

Objective: To characterize the effect of equipment changes in a longitudinal, multi-site multiple sclerosis trial.

Methods: Using data from a clinical trial in progressive multiple sclerosis, we explored how major changes in imaging hardware affected data. We analyzed the extent to which these changes affected imaging biomarkers and the estimated treatment effects by including such changes as a time-dependent covariate.

Results: Significant differences whole brain atrophy (brain parenchymal fraction, BPF) and microstructure (transverse diffusivity, TD) between scans with and without changes were found and depended on the type of hardware change. A switch from GE HDxt to Siemens Skyra led to significant shifts in BPF (p < 0.04) and TD (p < 0.0001). However, we could not detect the influence of hardware changes on overall trial outcomes- differences between placebo and treatment arms in change over time of BPF and TD (p > 0.5).

Conclusions: The results suggest that differences among hardware types should be considered when planning and analyzing brain atrophy and diffusivity in a longitudinal clinical trial.
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http://dx.doi.org/10.1177/20552173211010843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138298PMC
May 2021

A New Way to Identify Promising Therapies for Progressive Multiple Sclerosis.

Neurology 2021 05 23;96(18):833-834. Epub 2021 Mar 23.

From the Mellen Center for Multiple Sclerosis Treatment and Research (R.J.F.), Neurological Institute, Cleveland Clinic, OH; and Department of Statistics and Sanders Brown Center on Aging (R.J.K.), University of Kentucky, Lexington.

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http://dx.doi.org/10.1212/WNL.0000000000011862DOI Listing
May 2021

How common is active inflammation in progressive multiple sclerosis?

Authors:
Robert J Fox

Nat Rev Neurol 2021 Aug;17(8):463-464

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

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http://dx.doi.org/10.1038/s41582-021-00518-4DOI Listing
August 2021

Natalizumab in Early Relapsing-Remitting Multiple Sclerosis: A 4-Year, Open-Label Study.

Adv Ther 2021 07 20;38(7):3724-3742. Epub 2021 May 20.

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

Introduction: STRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative) relapsing-remitting multiple sclerosis (RRMS) patients with disease duration ≤ 3 years. The objective of STRIVE was to examine no evidence of disease activity (NEDA) status and predictors of NEDA in natalizumab-treated patients with early RRMS.

Methods: Proportions of patients with NEDA were evaluated along with baseline predictors of NEDA, annualized relapse rate, 24-week confirmed disability worsening (CDW), magnetic resonance imaging assessments (T2 and gadolinium-enhancing lesions), and serious adverse events.

Results: In years 1 and 2, 56.1% (95% confidence interval [CI] 48.7-63.4%) and 73.6% (95% CI 66.2-80.2%) of patients (intent-to-treat population [N = 222]), respectively, achieved NEDA. In years 3 and 4, 84.6% (95% CI 78.0-89.9%) and 91.9% (95% CI 86.4-95.8%) of patients, respectively, achieved Clinical NEDA (no relapses or 24-week CDW). Baseline predictors of NEDA in year 4 were Expanded Disability Status Scale score ≤ 2.0 (odds ratio [OR] = 3.85 [95% CI 1.54-9.63]; p = 0.004) and T2 lesion volume > 4 cc (OR = 0.39 [95% CI 0.15-0.98]; p = 0.046), with the latter also predicting Clinical NEDA in year 4 (OR = 0.21 [95% CI 0.05-0.92]; p = 0.038). The cumulative probability of CDW at year 4 was 19.3%. Serious adverse events were reported in 11.3% of patients.

Conclusion: These results support the long-term safety and effectiveness of natalizumab. Baseline predictors of NEDA help to inform benefit-risk assessments of natalizumab treatment in JCV-negative patients with early RRMS.

Trial Registration: ClinicalTrials.gov identifier NCT01485003.
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http://dx.doi.org/10.1007/s12325-021-01722-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279996PMC
July 2021

Sensitivity of T1/T2-weighted ratio in detection of cortical demyelination is similar to magnetization transfer ratio using post-mortem MRI.

Mult Scler 2021 May 20:13524585211014760. Epub 2021 May 20.

Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Background: Detecting cortical demyelination using magnetic resonance imaging (MRI) in multiple sclerosis (MS) remains a challenge. Magnetization transfer ratio (MTR), T1-weighted/T2-weighted ratio (T1T2R), and T2-weighted (T2w) signal are sensitive to cortical demyelination, but their accuracy is unknown.

Objectives: To quantify the sensitivity, specificity, and accuracy of postmortem T1T2R, MTR, and T2w in detecting cortical demyelination.

Methods: postmortem MRIs from 9 patients were used to measure T1T2R, MTR, and T2w along the midline of cortical gray matter and classified as normal or abnormal. MRIs were co-registered and compared to hemispheric myelin staining. The sensitivity, specificity, and accuracy of T1T2R, MTR, and T2w in detecting cortical demyelination were measured.

Results: The mean age (standard deviation) at death was 64.7 (+/-13.7) years with a disease duration of 23.8 (+/-10.5) years. The sensitivity was 78% for MTR, 75% for T1T2R, and 63% for T2w. The specificity was 46% (T2w), 13% (T1T2R), and 29% (MTR). The accuracy was 71% (T2w), 39% (MTR), and 42% (T1T2R). There were no significant differences between different MRI measures in cortical demyelination or intracortical/subpial lesion detection.

Conclusions: Although somewhat sensitive, the modest specificity of conventional MRI modalities for cortical demyelination indicates that they are influenced by cortical changes other than demyelination. Improved acquisition and post-processing are needed to reliably measure cortical lesion load.
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http://dx.doi.org/10.1177/13524585211014760DOI Listing
May 2021

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

A longitudinal assessment of depression and anxiety in the Republic of Ireland before and during the COVID-19 pandemic.

Psychiatry Res 2021 06 31;300:113905. Epub 2021 Mar 31.

Trinity Centre for Global Health, Trinity College Dublin, Ireland.

Few studies have examined changes in mental health before and after the outbreak of COVID-19. We examined changes in the prevalence of major depression and generalized anxiety disorder (GAD) between February 2019 and March-April 2020; if there were changes in major depression and GAD during six weeks of nationwide lockdown; and we identified factors that predicted major depression and GAD across the six-week lockdown period. Nationally representative samples of Irish adults were gathered using identical methods in February 2019 (N = 1020) and March-April 2020 (N = 1041). The latter was reassessed six weeks later. Significantly more people screened positive for depression in February 2019 (29.8% 95% CI = 27.0, 32.6) than in March-April 2020 (22.8% 95% CI = 20.2, 25.3), and there was no change in GAD. There were no significant changes in depression and GAD during the lockdown. Major depression was predicted by younger age, non-city dwelling, lower resilience, higher loneliness, and higher somatic problems. GAD was predicted by a broader set of variables including several COVID-19 specific variables. These findings indicate that the prevalence of major depression and GAD did not increase as a result of, or during the early phase of the COVID-19 pandemic in Ireland.
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http://dx.doi.org/10.1016/j.psychres.2021.113905DOI Listing
June 2021

Maternal Opioid Exposure Culminates in Perturbed Murine Neurodevelopment and Hyperactive Phenotype in Adolescence.

Neuroscience 2021 05 31;463:272-287. Epub 2021 Mar 31.

Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Center for Addiction Research, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States. Electronic address:

Opioid use by women during pregnancy has risen dramatically since 2004, accompanied by a striking increase in the prevalence of neonatal opioid withdrawal syndrome (NOWS) and other long-term neurological deficits. However, the mechanisms underlying the impact of prenatal opioid exposure on fetal neurodevelopment are largely unknown. To translate from the clinical presentation, we developed a novel mouse model to study the neurodevelopmental consequences of maternal opioid use and management. Female mice were treated with oxycodone (OXY) before mating to mimic opioid use disorder (OUD) in humans. Following pregnancy confirmation, dams were switched to buprenorphine (BUP) via oral administration, simulating medication management of OUD (MOUD) in pregnant women. Here, we document critical changes in fetal brain development including reduced cortical thickness, altered corticogenesis, and ventriculomegaly in embryos from dams that were treated with opioids before and throughout pregnancy. Maternal care giving behavior was slightly altered without affecting gross growth of offspring. However, adolescent offspring exposed to maternal opioid use during pregnancy exhibited hyperactivity in late adolescence. Remarkably, we also show increased generation of dopaminergic neurons within the ventral tegmental area (VTA) of mice exposed to prenatal opioids. These data provide critical evidence of teratogenic effects of opioid use during pregnancy and suggest a causal relationship between maternal opioid use and neurodevelopmental/behavioral anomalies in adolescence.
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http://dx.doi.org/10.1016/j.neuroscience.2021.03.014DOI Listing
May 2021

Axial Articular Manifestations in Primary Sjögren Syndrome: Have We Been Missing Spondyloarthritis for All This Time?

J Rheumatol 2021 Jul 1;48(7):963-964. Epub 2021 Apr 1.

R.I. Fox, MD, PhD, Chief, C.M. Fox, RN, Division of Rheumatology, Scripps Memorial and Research Foundation, La Jolla, California, USA.

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http://dx.doi.org/10.3899/jrheum.201175DOI Listing
July 2021

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 May;78(5):558-567

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
May 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455719PMC
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 06;78(6):699-708

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
June 2021

Posttraumatic stress disorder and loneliness are associated over time: A longitudinal study on PTSD symptoms and loneliness, among older adults.

Psychiatry Res 2021 05 2;299:113846. Epub 2021 Mar 2.

Department of Psychology, Maynooth University, Kildare, Ireland.

Loneliness has a pernicious effect on mental health in later life and is likely to have a bidirectional relationship with psychopathology. However, longitudinal research examining loneliness and posttraumatic stress symptoms among older adults is scarce. This study aimed to examine the longitudinal relationship between different types of loneliness (social and emotional) and posttraumatic stress symptoms. Using two waves of an older adult sample (n = 1,276) from the Longitudinal Aging Study Amsterdam (LASA), this longitudinal relationship was examined using a multivariate two wave-latent change score (2W-LCS) model. There were significant, however, very small increases in both posttraumatic stress symptoms and emotional loneliness over time, whereas, average social loneliness scores did not significantly increase/decrease over time. Changes in both social (β = .16) and emotional loneliness (β = .15) were associated with small changes in posttraumatic stress symptoms, consistent with the existence of a longitudinal association between the constructs, net of covariate effects. Results provide evidence of the existence of a longitudinal association between subtypes of loneliness and posttraumatic stress symptoms, among older adults. Results have implications for clinicians who should identify individuals at risk of developing posttraumatic stress symptoms, and for the theory of both posttraumatic stress disorder and loneliness.
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http://dx.doi.org/10.1016/j.psychres.2021.113846DOI Listing
May 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387506PMC
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 04 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
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