Jeffrey Dunn, MD

All Publications

• Autoimmune Hepatitis During Treatment of Multiple Sclerosis with Alemtuzumab Carlson, A., Bozinov, N., Kipp, L., Dunn, J., Lock, C. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090804181

• Infectious Complications of Multiple Sclerosis Therapies: Implications for Screening, Prophylaxis, and Management. Open forum infectious diseases Epstein, D. J., Dunn, J., Deresinski, S. 2018; 5 (8): ofy174

  Abstract

  Multiple sclerosis therapies include interferons, glatiramer, and multiple immunosuppressive drugs. Discerning infectious risks of immunosuppressive drugs requires understanding their mechanisms of action and analyzing interventional studies and postmarketing observational data. Though identical immunosuppressive therapies are sometimes used in non-neurologic conditions, infectious risks may differ in this population. Screening for and treatment of latent tuberculosis (TB) infection should be prioritized for patients receiving alemtuzumab; ocrelizumab is likely not associated with an increased risk of TB. Hepatitis B virus (HBV) reactivation can be devastating for patients treated with ocrelizumab and alemtuzumab, whereas the small molecule oral agents do not likely pose substantial risk of HBV. Progressive multifocal leukoencephalopathy is a particular concern with natalizumab. Alemtuzumab, and possibly natalizumab and fingolimod, risks herpes virus reactivation and may warrant prophylaxis. Unusual opportunistic infections have been described. Vaccination is an important tool in preventing infections, though vaccine timing and contraindications can be complex.

  View details for DOI 10.1093/ofid/ofy174

  View details for PubMedID 30094293

  View details for PubMedCentralID PMC6080056

• Ocrelizumab versus Interferon beta 1a in Relapsing Multiple Sclerosis New England Journal of Medicine Hauser, S. L., OPERA Clinical Investigators , et al 2017; 376 (3): 221-234

  View details for DOI 10.1056/NEJMoa1601277

• Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology Giovannoni, G., Cohen, J. A., Coles, A. J., Hartung, H. P., Havrdova, E., Selmaj, K. W., Margolin, D. H., Lake, S. L., Kaup, S. M., Panzara, M. A., Compston, D. A. 2016; 87 (19): 1985–92

  Abstract

  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 Schubert, R. D., Hu, Y., Kumar, G., Szeto, S., Abraham, P., Winderl, J., Guthridge, J. M., Pardo, G., Dunn, J., Steinman, L., Axtell, R. C. 2015; 194 (5): 2110-2116

  Abstract

  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 Hua, L. H., Lee, J., Dorfman, L., Dunn, J. SAGE PUBLICATIONS LTD. 2014: 920

  View details for Web of Science ID 000337854400083

• 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 Schubert, R., Goodyear, A., Abraham, P., Dunn, C., Steinman, L., Dunn, J., Axtell, R. 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 Lublin, F., CombiRx Investigators 2013; 73 (3): 327-340
• Mobility Concerns in Multiple Sclerosis US Neurology Lee, J., Dunn, J. 2013; 9 (1): 17-23
• Disease modifying therapies for non relapsing Multiple Sclerosis Neurol Clin Pract Dunn, J. 2013; December (3): 515-518
• Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial LANCET Coles, A. J., Twyman, C. L., Arnold, D. L., Cohen, J. A., Confavreux, C., Fox, E. J., Hartung, H., Havrdova, E., Selmaj, K. W., Weiner, H. L., Miller, T., Fisher, E., Sandbrink, R., Lake, S. L., Margolin, D. H., Oyuela, P., Panzara, M. A., Compston, D. A. 2012; 380 (9856): 1829-1839

  Abstract

  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 Herges, K., de Jong, B. A., Kolkowitz, I., Dunn, C., Mandelbaum, G., Ko, R. M., Maini, A., Han, M. H., Killestein, J., Polman, C., Goodyear, A. L., Dunn, J., Steinman, L., Axtell, R. C. 2012; 18 (4): 398-408

  Abstract

  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 Herges K, DeJong BA, Kolkowitz I, Dunn C, Mandelbaum G, Maini A, Han M, Killestein J, Polman C, Goodyear A, Dunn J, Steinman L, Axtell RC 2012; 18 (4): 398-408
• Alemtuzumab for patients with relapsing Multiple Sclerosis after disease modifying therapy: a randomized controlled Phase 3 trial. Lancet A, C. J., CARE MS II, I. 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 Dunn, J., Blight, A. 2011; 27 (7): 1415-1423

  Abstract

  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 Dunn J, Blight A 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 Dunn, J. 2010; 10 (4): 433-440

  Abstract

  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 LANCET NEUROLOGY Wynn, D., Kaufman, M., Montalban, X., Vollmer, T., Simon, J., Elkins, J., O'Neill, G., Neyer, L., Sheridan, J., Wang, C., Fong, A., Rose, J. W. 2010; 9 (4): 381-390

  Abstract

  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. Dunn, J. 2010; 10 (4): 433-440
• Cytomegalovirus Infection with MRI Signal Abnormalities Affecting the Optic Nerves, Optic Chiasm, and Optic Tracts JOURNAL OF NEURO-OPHTHALMOLOGY Pershing, S., Dunn, J., Khan, A., Liao, Y. J. 2009; 29 (3): 223-226

  Abstract

  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 Pershing S, D. K. 2009; 29 (3): 223-226
• Glatiramer Acetate after Induction Therapy with Mitoxantrone in Relapsing Multiple Sclerosis Multiple Sclerosis Vollmer T, P. B. 2008; Apr 18
• Tovaxin for Early Relapsing Multiple Sclerosis Phase 2b Placebo Controlled Trial of Autologous T cell vaccination in patients with CIS or RRMS Multiple Sclerosis Fox, E., The TERMS Study Investigators 2008; 14: S5-S27
• Glatiramer Acetate after Mitoxantrone Induction improves MRI markers of lesion volume and permanent tissue injury in MS J Neurol Arnold D., Campagnolo D., Panitch H., Bar-Or A., Dunn J, Freedman M., Gazda S.K., Vollmer T. 2008; 255: 1473-1478
• Daclizumab in Patients with Active Relapsing Multiple Sclerosis on Concurrent Interferon beta Therapy; Week 24 data Phase II ECTRIMS Montalban X, K. W. 2007; 10/11/07: S18
• Randomized, Double Blind, Dose Comparison Study of Glatiramer Acetate in Relapsing Remitting MS Neurology Cohen JA, R. G. 2007; 68 (12): 939-944
• Safety and Tolerability of Glatiramer Acetate in Pediatric Patients with Relapsing Remitting Multiple Sclerosis ECTRIMS/ACTRIMS Krupp L, Banwell B, Picone M, Dunn J, Weinstock-Guttman B, Pardo L. 2005: abstract
• Comprehensive Outpatient Management of Patients with Multiple Sclerosis RIMS MS Symposium Odderson I, D. 2001: abstract
• Novantrone in the Treatment of Multiple Sclerosis Alliance News Dunn Jeffrey, Kita M., Lucas S., Bowen J., 2001: 1-3
• Clinical Advisory Committee Statement Health Care Connection Bowen J., Dunn Jeffrey E., Kraft G.H., Ratley G., Shilling J., Smith C., Thompson L. 1999; I (1): 1-2
• Gingko Biloba in the Treatment of Alzheimer's Disease Alternative Medicine Dunn Jeffrey E., Maidan R., Pallis J. 1998; 1 (15): 1-2
• Atherosclerotic Aortic Disease as a Source of Embolic Infarct Journal of Neurovascular Disease Bursell John P.,Odderson I., Dunn Jeffrey E. 1996; 1 (2): 35-38
• INTRACEREBRAL BACILLARY ANGIOMATOSIS IN A PATIENT INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS ANNALS OF INTERNAL MEDICINE Spach, D. H., Panther, L. A., Thorning, D. R., Dunn, J. E., Plorde, J. J., MILLER, R. A. 1992; 116 (9): 740-742

  View details for Web of Science ID A1992HQ62300008

  View details for PubMedID 1558347

• Intracerebral Bacillary Angiomatosis in a Patient Infected with HIV Annals of Internal Medicine Spach, D., Panther L., Thorning D., Dunn Jeffrey E., Plorde J.L., Miller, R. 1992; 116: 740-743