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Jeffrey P Harris - One of the best experts on this subject based on the ideXlab platform.

  • paraneoplastic syndrome a masquerade of autoimmune Inner Ear Disease
    Otology & Neurotology, 2014
    Co-Authors: Jacqueline J Greene, Jeffrey P Harris, Michael W Keefe, Akihiro J Matsuoka
    Abstract:

    Rare and diagnostically challenging, paraneoplastic syndromes can appEar months to yEars before detection of their underlying neoplasms and are associated with rapidly progressive neurologic deficits, including cochleovestibulopathy and death. Less than 20 cases of paraneoplastic cochleovestibulopathy have been reported in the online database PubMed. We present three recent cases: one patient with a history of B-cell follicular lymphoma who developed dermatomyositis and hEaring loss before detection of lymphoma recurrence in his anterior chest wall, a second patient with sudden asymmetric hEaring loss, found to have a 12-cm renal mass before death, and a third with fluctuating bilateral hEaring loss who was ultimately found to have a thymoma. Although characterized as type VI (non-immune rapidly progressive sensorineural hEaring loss) within the Harris autoimmune Inner Ear Disease classification system, the mechanism of paraneoplastic cochleovestibulopathy is not well understood. Although specific anti-neuronal antibodies such as anti-Hu may be associated with other paraneoplastic neurologic disorders, these antibodies have limited diagnostic utility with paraneoplastic cochleovestibulopathy. Steroids have limited efficacy with regard to hEaring recovery, whereas intravenous immunoglobulin has been shown to be of benefit. These recent cases demonstrate how auditory and vestibular deficits may be indicative of a rare but potentially life-threatening occult neoplasm where timely diagnosis is critical. We believe that understanding paraneoplastic cochleovestibulopathy is of interest across a broad range of clinical practices.

  • Autoimmune Inner Ear Disease: a retrospective review of forty-seven patients.
    Audiology & neuro-otology, 2013
    Co-Authors: Akihiro J Matsuoka, Jeffrey P Harris
    Abstract:

    The purpose of this retrospective study was to characterize and further define autoimmune Inner Ear Disease (AIED) using the Harris AIED classification. A retrospective review was conducted at two tertiary medical centers for 47 patients who were diagnosed with AIED. The overall patient response rate to oral prednisone treatment was 69.7%. The sensitivity of the test for a serum antibody against heat-shock protein 70 (HSP70) was 54.5% and the specificity was 42.9%. Therefore, the clinical utility of the HSP70 antibody test appEared to be limited with respect to the diagnosis of AIED. Vertigo, tinnitus and aural fullness improved significantly with both of the newly developed adalimumab (Humira®) and rituximab (Rituxan®). However, hEaring loss did not improve in the present study.

  • autoimmune Inner Ear Disease a retrospective review of forty seven patients
    Audiology and Neuro-otology, 2013
    Co-Authors: Akihiro J Matsuoka, Jeffrey P Harris
    Abstract:

    The purpose of this retrospective study was to characterize and further define autoimmune Inner Ear Disease (AIED) using the Harris AIED classification. A retrospective review was conducted at two ter

  • a pilot study of rituximab in immune mediated Inner Ear Disease
    Audiology and Neuro-otology, 2011
    Co-Authors: Stanley N Cohen, Mitchell Lowenstein, Angela G Shoup, Arthur Kavanaugh, Herbert Silverstein, Peter S Roland, Jeffrey P Harris
    Abstract:

    Immune-mediated Inner Ear Disease (IMED) is a cause of rapidly progressive auditory dysfunction. Patients are often responsive to high-dose corticosteroids and the Disease is believed to be mediated b

  • A pilot study of rituximab in immune-mediated Inner Ear Disease.
    Audiology & neuro-otology, 2010
    Co-Authors: Stanley N Cohen, Mitchell Lowenstein, Angela G Shoup, Arthur Kavanaugh, Herbert Silverstein, Peter S Roland, Jeffrey P Harris
    Abstract:

    Immune-mediated Inner Ear Disease (IMED) is a cause of rapidly progressive auditory dysfunction. Patients are often responsive to high-dose corticosteroids and the Disease is believed to be mediated by an antibody to Inner Ear proteins. To date, no therapies have proven effective as corticosteroid-sparing agents. Rituximab is a monoclonal antibody that depletes B cells, resulting in a reduction in autoantibody production. For that reason, rituximab was evaluated in a small pilot study in patients with IMED to see if there was a signal suggesting benefit. In all, 5/7 patients met the primary endpoint of an improvement in pure tone average (500-3000 Hz) by 10 dB in at least one Ear, or an improvement in word identification score by at least 12% at 24 weeks, both relative to screening precorticosteroid values after 1 course of treatment. No significant adverse events were reported. The results of this study suggest further evaluation of rituximab as a treatment for IMED is indicated.

Shresh Pathak - One of the best experts on this subject based on the ideXlab platform.

  • Monocytes, Macrophages, and Microglia and the Role of IL-1 in Autoimmune Inner Ear Disease (AIED)
    Current Otorhinolaryngology Reports, 2018
    Co-Authors: Andrea Vambutas, Shresh Pathak
    Abstract:

    Purpose of Review Autoimmune Inner Ear Disease (AIED) is a rare Disease of unknown etiology characterized by a sudden decline in hEaring. Although AIED is initially responsive to corticosteroid therapy, this response is lost over time. We recently demonstrated in a small cohort of corticosteroid-resistant AIED patients that IL-1 was overexpressed in the plasma and that IL-1 antagonism led to hEaring improvement and reduction in circulating IL-1. Autoinflammatory Diseases, such as Muckle-Wells syndrome (MWS), are Diseases of the innate immune system whose phenotype includes sensorineural hEaring loss. Monocytes are the primary cells orchestrating the inflammatory response in this family of Diseases, due to a gain-of-function mutation that causes excessive IL-1 release.

  • the balance of tissue inhibitor of metalloproteinase 1 and matrix metalloproteinase 9 in the autoimmune Inner Ear Disease patients
    Journal of Interferon and Cytokine Research, 2017
    Co-Authors: Logan Eisner, Andrea Vambutas, Shresh Pathak
    Abstract:

    Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a protein implicated in the control of inflammation in a number of autoimmune Diseases. We hypothesized that the balance of TIMP-1 and matrix metalloproteinase-9 (MMP-9) may influence the control or perpetuation of inflammation in corticosteroid-responsive (RES) and corticosteroid-resistant (NR) autoimmune Inner Ear Disease (AIED) patients. In the present study, we observed that plasma from AIED patients exhibited greater levels of TIMP-1 values compared with normal healthy controls. TIMP-1 abrogates lipopolysaccharide-mediated interleukin (IL)-1β release from peripheral blood mononuclEar cells in a dose-dependent manner. RES AIED patients have higher basal TIMP-1 levels and produce more TIMP-1 in response to IL-1β. Conversely, consistent with our previous studies, we found that NR patients have higher basal MMP-9 levels and produce more MMP-9 levels in response to IL-1β.

  • n acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune Inner Ear Disease patients
    Immunologic Research, 2015
    Co-Authors: Corey Stern, Shresh Pathak, Andrea Vambutas
    Abstract:

    Autoimmune Inner Ear Disease (AIED) is a poorly understood Disease marked by bilateral, rapidly progressive hEaring loss triggered by unknown stimuli, which is corticosteroid responsive in 60 % of patients. Although the mechanism of the Disease is not precisely understood, a complex interaction of cytokines is believed to contribute toward the inflammatory Disease process and hEaring loss. Previously, we showed the role of TNF-α in steroid-sensitive and IL-1β in steroid-resistant immune-mediated hEaring loss. N-Acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic sudden hEaring loss, where the addition of NAC resulted in better hEaring recovery than with steroids alone, although the mechanism of this protection was not elucidated. In the present study, we observed PBMCs from AIED patients exhibited higher baseline TNF-α and MPO levels compared with normal healthy controls. NAC effectively abrogates LPS-mediated TNF-α release from PBMC of both AIED patients and controls. We demonstrated that in AIED patients, the TNF-α downstream signaling pathway appEars aberrantly regulated, influencing both MPO and IL-8 expression. Given that NAC effectively abrogated LPS-mediated TNF-α release and exerted minimal effects on the downstream targets of this pathway, we feel NAC may be a rational adjunct therapy for this enigmatic Disease, worthy of clinical exploration.

  • Early efficacy trial of anakinra in corticosteroid resistant autoimmune Inner Ear Disease
    Journal of Clinical Investigation, 2014
    Co-Authors: Andrea Vambutas, Shresh Pathak, Martin Lesser, Virginia Mullooly, Gerald D Zahtz, Lisa Rosen, Elliot Goldofsky
    Abstract:

    BACKGROUND. Autoimmune Inner Ear Disease (AIED) is a rare Disease that results in progressive sensorineural hEaring loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals. METHODS. We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period. RESULTS. Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1β plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1β plasma levels. CONCLUSION. We demonstrated that IL-1β inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1β plasma levels associated with both clinical hEaring response and Disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1β inhibition is warranted. TRIAL REGISTRATION. ClinicalTrials.gov NCT01267994. FUNDING. NIH, Merrill & Phoebe Goodman Otology ResEarch Center, and Long Island HEaring & Speech Society.

  • il 1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune Inner Ear Disease
    Journal of Immunology, 2011
    Co-Authors: Shresh Pathak, Elliot Goldofsky, Esther X Vivas, Vincent R Bonagura, Andrea Vambutas
    Abstract:

    Autoimmune Inner Ear Disease is an enigmatic disorder characterized by recurring episodes of sudden or progressive sensorineural hEaring loss. HEaring loss can be improved by timely corticosteroid administration, but only half of those treated respond, and for many responders, that response is lost over time. The mechanisms that control corticosteroid responsiveness in this disorder are largely uncharacterized. We have previously identified that the induction by dexamethasone of IL-1R type II (IL-1R2) expression in PBMC predicts corticosteroid responsiveness in this disorder. In this study, we asked whether IL-1β was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1β expression or release in response to dexamethasone, as compared with nonresponders. IL-1β has been reported to induce matrix metalloproteinase-9 (MMP-9) expression. Given that metalloproteinases can cleave IL-1R2, we also asked whether MMP-9 expression was altered in this disorder. In this study, we demonstrate that corticosteroid nonresponders have elevated plasma levels of IL-1β and MMP-9 as compared with clinically responsive patients (p = 0.0008 and p = 0.037, respectively). Increasing MMP-9 expression correlated with increasing IL-1β concentration, suggesting that IL-1β expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1β. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1β release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1β into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1β release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1β release, suggesting that IL-1β blockade may be a viable therapy for these patients.

Gordon B. Hughes - One of the best experts on this subject based on the ideXlab platform.

  • safety of high dose corticosteroids for the treatment of autoimmune Inner Ear Disease
    Otology & Neurotology, 2009
    Co-Authors: Thomas H Alexander, Gordon B. Hughes, Julianna A Gulya, Maureen T Hannley, Michael H Weisman, Jennifer M Derebery, Paul E. Hammerschlag, Mark A. Espeland, Bruce J Gantz, Richard A Moscicki
    Abstract:

    Objective:To report the adverse effects associated with prolonged high-dose prednisone for the treatment of autoimmune Inner Ear Disease (AIED).Study Design:Prospective data collected as part of a multicenter, randomized, controlled trial for the treatment of corticosteroid-responsive AIED with meth

  • treatment of corticosteroid responsive autoimmune Inner Ear Disease with methotrexate a randomized controlled trial
    JAMA, 2003
    Co-Authors: Jeffrey P Harris, Gordon B. Hughes, Julianna A Gulya, Maureen T Hannley, Michael H Weisman, Jennifer M Derebery, Paul E. Hammerschlag, Mark A. Espeland, Bruce J Gantz, Richard A Moscicki
    Abstract:

    ContextA number of therapies have been proposed for the long-term management of corticosteroid-responsive, rapidly progressive, bilateral sensorineural hEaring loss (autoimmune Inner Ear Disease [AIED]). Methotrexate has emerged as the benchmark agent but has not been rigorously evaluated for hEaring improvement in patients with AIED.ObjectiveTo assess the efficacy of long-term methotrexate in maintaining hEaring improvements achieved with glucocorticoid (prednisone) therapy in patients with AIED.Design, Setting, and ParticipantsA randomized, double-blind, placebo-controlled trial conducted from February 3, 1998, to November 5, 2001, of 67 patients with rapidly progressive, bilateral sensorineural hEaring loss at 10 tertiary care centers in the United States.InterventionRandomization to either oral methotrexate (15 to 20 mg/wk; n = 33) or placebo (n = 34), in combination with an 18-week prednisone taper. Follow-up examinations, including audiometric evaluation, were performed at 4, 8, 12, 24, 36, 48, and 52 weeks, or until hEaring loss was documented.Main Outcome MeasureMaintenance of hEaring improvement achieved from prednisone treatment.ResultsSixty-seven patients (57.8%) enrolled in the prednisone challenge experienced hEaring improvement. Twenty-five patients (37%) experienced hEaring improvements in both Ears. Of the individuals who reached study end points, 24 (80%) of 30 end points were because of measured hEaring loss in the methotrexate group and 29 (93.5%) of 31 end points were because of measured hEaring loss in the placebo group (P = .15). Methotrexate was no more effective than placebo in maintaining the hEaring improvement achieved with prednisone treatment (hazard ratio, 1.31; 95% confidence interval, 0.79-2.17; P = .30).ConclusionMethotrexate does not appEar to be effective in maintaining the hEaring improvement achieved with prednisone therapy in patients with AIED.

  • Autoimmune Inner Ear Disease—A Real Entity?
    Clinics in Laboratory Medicine, 1997
    Co-Authors: Barbara P. Barna, Gordon B. Hughes
    Abstract:

    : Involvement of autoimmune mechanisms in sudden-onset, rapidly progressive, bilateral Inner Ear Disease is supported by the following evidence: (1) the Inner Ear contains immune cells and mediators (immunoglobulins); (2) animal models demonstrate Inner Ear damage after immunization with Inner Ear tissue; (3) experimental autoimmune Inner Ear Disease appEars to be transferable with sensitized T cells; (4) human SNHL can occur in the context of systemic immunologic Disease; (5) SNHL can be improved by immunosuppressive therapy; and (6) patients with SNHL demonstrate elevated immune responses to Inner Ear proteins/tissue preparations. There are also several reasons, however, why the above Inner Ear Disease cannot be termed "autoimmune": (1) in experimental models, Inner Ear damage may be produced during an in situ immune response to an irrelevant antigen; (2) histopathology is not yet extensive enough to confirm the role of immune cells and mediators in human Disease; (3) immune reactivity to an organ-specific antigen associated with the Inner Ear has not yet been identified. At this time, therefore, clinical Inner Ear Disease with evidence of immunologic involvement is termed "immune-mediated" rather than "autoimmune." IMIED is likely to represent a heterogeneous group of Diseases with multifactorial causes but a common endpoint. Diagnosis is made primarily by clinical profile in association with laboratory testing to rule out neoplasia or infection. Investigational laboratory immunoassays for antibodies to Inner Ear proteins or hsp 70 appEar to have promise for diagnosis or predicting clinical response to immunosuppressive treatment. Sensitivity and specificity of such assays have not yet been established.

  • autoimmune Inner Ear Disease a real entity
    Clinics in Laboratory Medicine, 1997
    Co-Authors: Barbara P. Barna, Gordon B. Hughes
    Abstract:

    Involvement of autoimmune mechanisms in sudden-onset, rapidly progressive, bilateral Inner Ear Disease is supported by the following evidence: (1) the Inner Ear contains immune cells and mediators (immunoglobulins); (2) animal models demonstrate Inner Ear damage after immunization with Inner Ear tissue; (3) experimental autoimmune Inner Ear Disease appEars to be transferable with sensitized T cells; (4) human SNHL can occur in the context of systemic immunologic Disease; (5) SNHL can be improved by immunosuppressive therapy; and (6) patients with SNHL demonstrate elevated immune responses to Inner Ear proteins/tissue preparations. There are also several reasons, however, why the above Inner Ear Disease cannot be termed "autoimmune": (1) in experimental models, Inner Ear damage may be produced during an in situ immune response to an irrelevant antigen; (2) histopathology is not yet extensive enough to confirm the role of immune cells and mediators in human Disease; (3) immune reactivity to an organ-specific antigen associated with the Inner Ear has not yet been identified. At this time, therefore, clinical Inner Ear Disease with evidence of immunologic involvement is termed "immune-mediated" rather than "autoimmune." IMIED is likely to represent a heterogeneous group of Diseases with multifactorial causes but a common endpoint. Diagnosis is made primarily by clinical profile in association with laboratory testing to rule out neoplasia or infection. Investigational laboratory immunoassays for antibodies to Inner Ear proteins or hsp 70 appEar to have promise for diagnosis or predicting clinical response to immunosuppressive treatment. Sensitivity and specificity of such assays have not yet been established.

  • Immune Inner Ear Disease
    Otolaryngology–Head and Neck Surgery, 1995
    Co-Authors: Gordon B. Hughes, Richard A Moscicki
    Abstract:

    Educational objectives: To diagnose and treat immune Inner Ear Disease.

Yasuya Nomura - One of the best experts on this subject based on the ideXlab platform.

Antonio Puccetti - One of the best experts on this subject based on the ideXlab platform.

  • Immune-Mediated Inner Ear Disease
    The Autoimmune Diseases, 2014
    Co-Authors: Claudio Lunardi, Antonio Puccetti
    Abstract:

    Inner Ear damage can be caused by viral infections, trauma, vascular damage, and immune mechanisms, and is responsible for sensorineural hEaring loss, a syndrome characterized by rapid progression of hEaring impairment that is frequently non-responsive to medical treatment. Immune-mediated Inner Ear Disease can be of autoimmune origin either as an isolated process affecting only the Ear, to be considered as an organ-specific autoimmune Disease, or as part of a systemic autoimmune disorder in approximately 30% of cases. The incidence and prevalence of autoimmune Inner Ear Disease is unknown due to the lack of reliable diagnostic tests and to the limited access to the site of autoimmune aggression. Since the rapid administration of steroids and/or other immunosuppressive agents may result in hEaring preservation, a great effort is needed in order to find both clinical and immunological features able to identify these patients. Animal models of autoimmune Inner Ear Disease may help in this effort to clarify the largely unknown pathophysiology of the Disease and the response to therapy.

  • Inner Ear Disease
    The Autoimmune Diseases, 2006
    Co-Authors: Claudio Lunardi, Antonio Puccetti
    Abstract:

    Publisher Summary It is now evident that the Inner Ear is not an “immunologically privileged” site and may mount an immune response against both foreign and self-antigens. This chapter focuses on sensorineural hEaring loss (SNHL). This has been described and termed in different ways: autoimmune SNHL, immunemediated Inner Ear Disease (IMIED), idiopathic progressive bilateral SNHL, sudden SNHL, and idiopathic SNHL, bilateral immune-mediated Meniere's Disease, autoimmune vestibulo-cochlEar disorders, generating a great confusion in the identification of patients and in the evaluation of different studies. The association of IMIED with systemic autoimmune Diseases provides evidence that autoimmunity can damage the Inner Ear, but it does not address organ-specific Disease. Antibodies directed against different Inner Ear antigens have been identified in some patients. However, they are neither diagnostic nor correlate with Disease state. In the future, the major goals for resEarch in this field can be the identification of pathogenetically relevant autoantigens, development of a highly specific diagnostic test, and a better knowledge of the immunopathologic mechanisms in an organ as inaccessible as the Inner Ear.