Jeffrey Dunn, MD serves as the Lily Sarafan Director of Neuroimmunology, Clinical Professor and Chief of Neuroimmunology within the Department of Neurology & Neurological Sciences at Stanford University. He specializes in the diagnosis, treatment and research of immune-mediated diseases of the central nervous system, including Multiple Sclerosis, transverse myelitis, and Neuromyelitis Optica. Dr. Dunn is regarded nationally as among the foundational leaders in his field and is an elected Fellow of the American Academy of Neurology. He is the past Chair of the MS Section of the AAN. As Principal Investigator in more than 30 clinical research trials, Dr. Dunn has helped usher in new and improved immunotherapies for Multiple Sclerosis. He is the architect of Project BIG (see www.projectbig.com), an interdisciplinary research collaborative with Stanford scientists to identify biomarkers and candidate therapeutic targets within the paradigm of precision medicine. These collaborations have yielded such pivotal discoveries as EBV viral molecular mimicry as a driver of MS pathogenesis, a discovery recognized by the American Association for the Advancement of Science as a runner-up Science Breakthrough of the Year in 2022; and a T lymphocyte subtype having a key role in modulating human autoimmunity. Dr. Dunn is a US patent holder for a marker of MS treatment response with co-inventors, and has authored or co-authored more than 50 peer-reviewed manuscripts and abstracts. Dr. Dunn has been recognized for excellence in clinical teaching, as a 12 time winner of the Neurology Clerkship student teaching award, the Lysia Forno Award recipient for excellence in Neurology resident teaching, and by Arthur Bloomfield Awards and the Henry J. Kaiser Family Foundation. In recognition of his dedication to the educational mission, his name is given to the eponymous Fishers-Dunn Prize, awarded annually to best medical student teaching among active Neurology residents. His formative contributions to medical education were recognized by the inaugural Oscar Salvatierra Award for exceptional service to Stanford medical students awarded by the Stanford University School of Medicine.
- Multiple Sclerosis
- Neuromyelitis Optica
- Transverse Myelitis
Clinical Professor, Neurology & Neurological Sciences
Lily Sarafan Director of Neuroimmunology, Stanford University Department of Neurology (2022 - Present)
Chief, Division of Neuroimmunology, Department of Neurology & Neurological Sciences (2009 - Present)
Chair, Multiple Sclerosis Section; American Academy of Neurology (2018 - 2020)
Neurology Clerkship Director, Stanford University School of Medicine (2008 - 2019)
Board Member, National Medical Advisory Committee, National Multiple Sclerosis Society (2018 - 2021)
Fellowship Director, Clinical Neuroimmunology Fellowship Program; Stanford University (2010 - 2017)
Honors & Awards
Certificate of Special Congressional Recognition, US Congress (CA-04) (2023)
Neurology Clerkship Teaching Award, Stanford University Neurology (2022-2023)
Science Breakthrough of the Year, runner-up, American Association for the Advancement of Science (2022)
Oscar Salvatierra Award for Exceptional Service to Medical Students and the School of Medicine, Stanford University School of Medicine (2021)
Neurology Clerkship Teaching Award, Stanford University Neurology (2019-2020)
A. B. Baker National Teacher of the Year Recognition Award, American Academy of Neurology (2019)
Healthcare Partner of the Year, National Multiple Sclerosis Society, NorCal (2019)
Arthur L. Bloomfield Award in Recognition of Excellence in Teaching Clinical Medicine, Stanford University School of Medicine (2017)
Special Commendation for outstanding care, research and contributions to the MS community, California State Senate (2016)
Henry J. Kaiser Family Foundation Award for Excellence in Clinical Teaching, Stanford University School of Medicine (2013)
Top Doctors: the top doctors in the US as nominated by their peers, Castle Connolly (2012-2023 inclusive)
AUPN Neurology highest percentage National Recruitment Award, Association of University Professors of Neurology (2012, 2011)
Excellence in Teaching Award, Stanford University School of Medicine (2011-2012)
Arthur L. Bloomfield Award in Recognition of Excellence in the Teaching of Clinical Medicine, Stanford University School of Medicine (2011)
Excellence in Teaching Award, Stanford University School of Medicine (2010-2011)
Excellence in Teaching Award, Stanford University School of Medicine (2009-2010)
Fellow, American Academy of Neurology (2008-present)
Excellence in Neurology Clerkship Teaching Award, Stanford University Neurology (2008-2017 inclusive)
Lysia K. Forno Award for Excellence in Teaching Neurology Residents, Stanford University Department of Neurology & Neurosciences (2008-2009)
America's Top Rated Physicians, Guide to Top Doctors (1998-2007 inclusive)
Boards, Advisory Committees, Professional Organizations
Fellow, American Academy of Neurology (2007 - Present)
Member, International Society of Neuroimmunology (2022 - Present)
Member, Consortium of MS Centers (2008 - Present)
Member, San Francisco Neurological Society (2009 - Present)
Board Certification: American Board of Psychiatry and Neurology, Neurology (1994)
Residency: University of Washington Medical Center (1993) WA
Medical Education: Temple University School of Medicine (1989) PA
B.A., Haverford College, French Literature (1983)
+, Institut d'Études Françaises, Avignon, France (1982)
Community and International Work
Orphan Outreach, Nairobi, Kenya, Africa
Opportunities for Student Involvement
Internation Journal of MS Care
Consortium of MS Centers
Opportunities for Student Involvement
Jeffrey Edward Dunn, Ryan D. Schubert, Robert C. Axtell. "United States Patent 10,054,588 Marker for determination of patient responsiveness", Leland Stanford Junior University, Aug 21, 2018
Current Research and Scholarly Interests
Translational research in the human application of emerging immunotherapies for neurological disease, focusing on Multiple Sclerosis, CIS, transverse myelitis and Neuromyelitis Optica (NMO). Collaborative research with Stanford and extramural scientific faculty to identify biomarkers of disease activity and treatment response in humans. Clinical trials to assess efficacy of emerging treatments for MS, CIS and NMO.
A Rollover Study to Evaluate the Long-Term Safety and Efficacy of Ocrelizumab In Patients With Multiple Sclerosis
This is a Phase IIIb, single-arm, multicenter, OLE study. Participants receiving ocrelizumab as an investigational medicinal product (IMP) in a Roche sponsored Parent study who continue to receive ocrelizumab or are in safety follow-up at the time of the closure of their respective Parent study (WA21092, WA21093 or WA25046) are eligible for enrollment in this extension study. Participants who will continue ocrelizumab treatment will receive IMP based on the dosage and administration received at the time of rollover from the Parent study.
Best Available Therapy Versus Autologous Hematopoetic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS)
This is a multi-center prospective rater-masked (blinded) randomized controlled trial of 156 participants, comparing the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio. All participants will be followed for 72 months after randomization (Day 0, Visit 0).
Project BIG, Stanford University and Sarafan ChEM-H
An interdisciplinary research collaborative to investigate the brain, immune system and gut mechanisms pertaining to the cause and treatment of Multiple Sclerosis and related neuroimmune disorders.
- May Han, Associate Professor, Stanford Neuroimmunology
- Lucas Kipp, Neurology & Neurological Sciences
- Tobias Lanz, Assistant Professor of Medicine (Immunology and Reumatology), Stanford
- Mark Davis, Director, Stanford Institute for Immunity, Transplantation and Infection and the Burt and Marion Avery Family Professor, Stanford University
- Jamie C. McDonald, Clinical Assistant Professor, Stanford University
For More Information:
Independent Studies (5)
- Directed Reading in Neurology and Neurological Science
NENS 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Neurology and Neurological Sciences
NENS 280 (Aut, Win, Spr, Sum)
- Graduate Research
NENS 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
NENS 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
NENS 199 (Aut, Win, Spr, Sum)
- Directed Reading in Neurology and Neurological Science
Postdoctoral Faculty Sponsor
- SARS-CoV-2 Vaccine Immune Response on Anti-Complement Therapy, Eculizumab LIPPINCOTT WILLIAMS & WILKINS. 2023
- Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) in conjunction with Allogeneic Bone Marrow Transplantation and Autoimmune Neutropenia: A study of two companion cases and institutional review of the MOGAD clinical phenotype spectrum LIPPINCOTT WILLIAMS & WILKINS. 2023
Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results from Randomized Phase 2b Core and Extension Studies.
To evaluate the dose-response relationship of 10, 20 and 40-mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in relapsing-remitting multiple sclerosis (RRMS) patients.In the Core study, 464 patients were randomized (1:1:1:1): placebo (n=121), 10-mg (n=108), 20-mg (n=116), or 40-mg ponesimod (n=119) once-daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks), TP2 and TP3 (up to 432 weeks). The 40-mg dose was discontinued due to low tolerability at the end of TP1 and 10-mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated.A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg=139, 20 mg=145, 40 mg=151) at any time during the Core and/or the Extension study. As of 31 March 2019, 214 patients were still on ponesimod treatment. Median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod 20-mg, from Core up to end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9% and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%).The effects on MS disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified.This study provides Class IV evidence that in individuals with relapsing-remitting multiple sclerosis, long-term treatment with ponesimod 20mg was associated with sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free.EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study).
View details for DOI 10.1212/WNL.0000000000200606
View details for PubMedID 35667837
Biomarker panel increases accuracy for identification of an MS relapse beyond sNfL.
Multiple sclerosis and related disorders
2022; 63: 103922
BACKGROUND: For relapsing-remitting multiple sclerosis (RRMS), there is a need for biomarker development beyond clinical manifestations and MRI. Soluble neurofilament light chain (sNfL) has emerged as a biomarker for inflammatory activity in RRMS. However, there are limitations to the accuracy of sNfL in identifying relapses. Here, we sought to identify a panel of biomarkers that would increase the precision of distinguishing patients in relapse compared to sNfL alone.METHODS: We used a multiplex approach to measure levels of 724 blood proteins in two distinct RRMS cohorts. Multiple t-tests with covariate correction determined biomarkers that were differentially regulated in relapse and remission. Logistic regression models determined the accuracy of biomarkers to distinguish relapses from remission.RESULTS: The discovery cohort identified 37 proteins differentially abundant in active RRMS relapse compared to remission. The verification cohort confirmed four proteins, including sNfL, were altered in active RRMS relapse compared to remission. Logistic regression showed that the 4-protein panel identified active relapse with higher accuracy (AUC=0.87) than sNfL alone (AUC=0.69).CONCLUSION: Our studies confirmed that sNfL is elevated during relapses in RRMS patients. Furthermore, we identified three other blood proteins, uPA, hK8 and DSG3 that were altered during relapse. Together, these four biomarkers could be used to monitor disease activity in RRMS patients.
View details for DOI 10.1016/j.msard.2022.103922
View details for PubMedID 35671674
A case of MOG antibody disoorder with pontine involvement mimicking CLIPPERS and extensive transverse myelitis
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000894020500090
KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.
Science (New York, N.Y.)
Here we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from celiac disease patients' leukocytes in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, which correlated with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity post infection. Our results indicate that in both species, these regulatory CD8+ T cells act uniquely to suppress pathogenic T cells in autoimmune and infectious diseases.
View details for DOI 10.1126/science.abi9591
View details for PubMedID 35258337
Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM.
Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.
View details for DOI 10.1038/s41586-022-04432-7
View details for PubMedID 35073561
Consensus Curriculum for Fellowship Training in Multiple Sclerosis and Neuroimmunology.
Neurology. Clinical practice
2021; 11 (4): 352-357
Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.
View details for DOI 10.1212/CPJ.0000000000001040
View details for PubMedID 34484933
Defining the Neuroimmunology/Multiple Sclerosis Subspecialty: Surveys of Fellowship Training in the United States
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000536058001053
Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis.
Journal of neuroinflammation
2020; 17 (1): 189
To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures.The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked.Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells.Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS.Parent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.
View details for DOI 10.1186/s12974-020-01847-9
View details for PubMedID 32539719
The North American Registry for Care and Research in Multiple Sclerosis
SAGE PUBLICATIONS LTD. 2019: 79–80
View details for Web of Science ID 000468918500171
- Infectious Complications of Multiple Sclerosis Therapies: Implications for Screening, Prophylaxis, and Management OPEN FORUM INFECTIOUS DISEASES 2018; 5 (8)
Autoimmune Hepatitis During Treatment of Multiple Sclerosis with Alemtuzumab
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000453090804181
Ocrelizumab versus Interferon beta 1a in Relapsing Multiple Sclerosis
New England Journal of Medicine
2017; 376 (3): 221-234
B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).
View details for DOI 10.1056/NEJMoa1601277
Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients.
2016; 87 (19): 1985-1992
To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
View details for DOI 10.1212/WNL.0000000000003319
View details for PubMedID 27733571
IFN-ß Treatment Requires B Cells for Efficacy in Neuroautoimmunity.
Journal of immunology
2015; 194 (5): 2110-2116
IFN-β remains the most widely prescribed treatment for relapsing remitting multiple sclerosis. Despite widespread use of IFN-β, the therapeutic mechanism is still partially understood. Particularly, the clinical relevance of increased B cell activity during IFN-β treatment is unclear. In this article, we show that IFN-β pushes some B cells into a transitional, regulatory population that is a critical mechanism for therapy. IFN-β treatment increases the absolute number of regulatory CD19(+)CD24(++)CD38(++) transitional B cells in peripheral blood relative to treatment-naive and Copaxone-treated patients. In addition, we found that transitional B cells from both healthy controls and IFN-β-treated MS patients are potent producers of IL-10, and that the capability of IFN-β to induce IL-10 is amplified when B cells are stimulated. Similar changes are seen in mice with experimental autoimmune encephalomyelitis. IFN-β treatment increases transitional and regulatory B cell populations, as well as IL-10 secretion in the spleen. Furthermore, we found that IFN-β increases autoantibody production, implicating humoral immune activation in B cell regulatory responses. Finally, we demonstrate that IFN-β therapy requires immune-regulatory B cells by showing that B cell-deficient mice do not benefit clinically or histopathologically from IFN-β treatment. These results have significant implications for the diagnosis and treatment of relapsing remitting multiple sclerosis.
View details for DOI 10.4049/jimmunol.1402029
View details for PubMedID 25646307
View details for PubMedCentralID PMC4340715
MRI CHARACTERISTICS OF CNS DEMYELINATING DISEASE IN ETHNIC INDIAN PATIENTS
SAGE PUBLICATIONS LTD. 2014: 920
View details for Web of Science ID 000337854400083
Disease-modifying therapies for nonrelapsing multiple sclerosis: Absence of evidence does not constitute evidence of absence.
Neurology. Clinical practice
2013; 3 (6): 515–18
View details for PubMedID 30107021
Analysis of B Cell Subsets in Multiple Sclerosis Patients on Immunomodulatory Therapy Reveals Modulation of CD19+CD24hiCD38hi Cells with Implications for the Diagnosis and Monitoring of MS
LIPPINCOTT WILLIAMS & WILKINS. 2013
View details for Web of Science ID 000332068602192
- Randomized study combining interferon and glatiramer acetate in Multiple Sclerosis Annals of Neurology 2013; 73 (3): 327-340
- Mobility Concerns in Multiple Sclerosis US Neurology 2013; 9 (1): 17-23
- Disease modifying therapies for non relapsing Multiple Sclerosis Neurol Clin Pract 2013; December (3): 515-518
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
2012; 380 (9856): 1829-1839
The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.Genzyme (Sanofi) and Bayer Schering Pharma.
View details for DOI 10.1016/S0140-6736(12)61768-1
View details for Web of Science ID 000311435000028
View details for PubMedID 23122650
Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein
MULTIPLE SCLEROSIS JOURNAL
2012; 18 (4): 398-408
The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-β treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-β, in contrast to disease induced with Th1 where treatment attenuated symptoms.This study demonstrates the similarities between NMO and Th17 EAE and how neutrophils mediate pathology in Th17 disease.Levels of blood biomarkers in NMO were assessed by Luminex and ELISA. Effects of IFN-β on neutrophils were assessed by culture assays and immunofluorescence. EAE was induced by transfer of myelin-specific Th1 or Th17 cells and treated with Sivelestat sodium hydrate, a neutrophil elastase inhibitor.We show Th17 cytokines, granulocyte chemokines, type 1 interferon and neutrophil elastase are elevated in patients with definitive NMO. In culture, we find that IFN-β stimulates neutrophils to release neutrophil elastase. In Th17 EAE, we demonstrate neutrophilic infiltration in the optic nerve and spinal cord which was not present in Th1 EAE. Blockade of neutrophil elastase with Sivelestat had efficacy in Th17 EAE but not Th1 EAE.The similarities between Th17 EAE and NMO indicate that this model represents several aspects of NMO. Neutrophils are critical in the pathologies of both Th17-EAE and NMO, and therefore blockade of neutrophil elastase is a promising target in treating NMO.
View details for DOI 10.1177/1352458512440060
View details for Web of Science ID 000302289900006
View details for PubMedID 22343184
View details for PubMedCentralID PMC3319834
- Protective Effect of elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin olidodendrocyte glycoprotein Multiple Sclerosis 2012; 18 (4): 398-408
- Alemtuzumab for patients with relapsing Multiple Sclerosis after disease modifying therapy: a randomized controlled Phase 3 trial. Lancet 2012; Nov 24 (380): 1829-1839
Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis
CURRENT MEDICAL RESEARCH AND OPINION
2011; 27 (7): 1415-1423
Multiple sclerosis (MS) can cause progressive walking impairment that contributes to disability, loss of independence, and reduced quality of life. Dalfampridine (4-aminopyridine), a voltage-dependent potassium channel blocker, has been shown to improve walking in patients with MS, as demonstrated by an increase in walking speed.To summarize knowledge about the mechanism of action of dalfampridine in the context of clinical evidence of walking improvement in MS patients.Although this was not a systematic review, which is the primary limitation of this study, searches of PubMed were performed using relevant search terms to identify studies that examined the mechanism of action related to MS and its effects in patients with MS in clinical trials.Voltage-gated potassium channels represent a family of related proteins that span cell membranes, open and close in response to changes in the transmembrane potential, and help regulate ionic potassium currents. Action potential conduction deficits in demyelinated axons result in part from the exposure after demyelination of the paranodal and internodal potassium channels that are distributed in the axonal membrane. This exposure leads to abnormal currents across the axonal membrane that can slow action potential conduction, result in conduction failure, or affect the axon's capacity for repetitive discharge. While dalfampridine is a broad-spectrum blocker of voltage-dependent potassium channels at millimolar concentrations, studies have shown improvement in action potential conduction in demyelinated axons at concentrations as low as 1 μM, and therapeutic plasma concentrations (associated with improved walking) are in the range of 0.25 µM. However, no specific potassium channel subtype has yet been characterized with significant sensitivity to dalfampridine in this range, and the effects of the drug at this low concentration appear to be quite selective. Improved conduction translates into clinical benefit as measured by objectively and subjectively assessed walking relative to placebo. Such improvements were observed in approximately one third of patients treated with an extended-release formulation of dalfampridine in clinical trials. These patients who responded to dalfampridine had an average increase in walking speed of approximately 25%, and greater improvements than nonresponders on a self-reported subjective measure of walking.The extended-release formulation of dalfampridine has been shown in clinical trials to improve walking speed in approximately one third of MS patients with ambulatory impairment. The putative mechanism of action of dalfampridine is restoration of action potential conduction via blockade of an as yet uncharacterized subset of potassium channels in demyelinated axons.
View details for DOI 10.1185/03007995.2011.583229
View details for Web of Science ID 000291662300014
View details for PubMedID 21595605
- Dalfampridine: A brief review of its Mechanism of Action and Efficacy as a treatment to improve walking in patients with Multiple Sclerosis Current Research Medical Opinion 2011; 27 (7): 1415-1423
Impact of mobility impairment on the burden of caregiving in individuals with multiple sclerosis
EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
2010; 10 (4): 433-440
Multiple sclerosis (MS) is a chronic, immune-mediated neurologic disease that typically strikes young adults during their most productive years, and is associated with a wide range of functional deficits and progressive disability. Loss of mobility is among the most disabling effects of MS, adversely affecting multiple outcomes, including independence, employment and quality of life. Relative to other common diseases, MS is associated with a disproportionately high socioeconomic burden. Informal and unpaid caregivers, such as family and friends, play a vital, sustained and often difficult role in supporting the ability of MS patients to live and function at home. However, there are few data characterizing caregiver burden in MS. This review was conducted to examine the need and impact of caregiving for patients with MS, focusing on the contribution of mobility impairment to loss of patient independence.
View details for DOI 10.1586/ERP.10.34
View details for Web of Science ID 000297009800017
View details for PubMedID 20482233
Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta
2010; 9 (4): 381-390
Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment.We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161.From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4.75 in the interferon beta and placebo group compared with 1.32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0.004) and 3.58 in the interferon beta and low-dose daclizumab group (25%, -76% to 68%; p=0.51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56(bright) natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0.002; interferon beta and high-dose daclizumab group p<0.0001). Common adverse events were equally distributed across groups.Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone.Facet Biotech and Biogen Idec.
View details for DOI 10.1016/S1474-4422(10)70033-8
View details for Web of Science ID 000276142000016
View details for PubMedID 20163990
- The impact of mobility impairment on the burden of caregiving in individuals with multiple sclerosis Expert Rev. Pharmacoeconomics Outcomes Res. 2010; 10 (4): 433-440
Cytomegalovirus Infection with MRI Signal Abnormalities Affecting the Optic Nerves, Optic Chiasm, and Optic Tracts
JOURNAL OF NEURO-OPHTHALMOLOGY
2009; 29 (3): 223-226
A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.
View details for Web of Science ID 000270048700011
View details for PubMedID 19726946
- CMV Optic Neuritis with Extensive Tracking along the Visual Pathway J Neuro-Ophthalmology 2009; 29 (3): 223-226
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- Glatiramer Acetate after Mitoxantrone Induction improves MRI markers of lesion volume and permanent tissue injury in MS J Neurol 2008; 255: 1473-1478
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- Randomized, Double Blind, Dose Comparison Study of Glatiramer Acetate in Relapsing Remitting MS Neurology 2007; 68 (12): 939-944
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