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Armstorfer M, Weitgasser L, Tschani S, Rösch S. [Cochlear implantation in patients with autoimmune hearing loss]. HNO 2025; 73:29-34. [PMID: 38647666 PMCID: PMC11711862 DOI: 10.1007/s00106-024-01472-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Autoimmune inner ear disease (AIED) manifests with recurrent fluctuating sensorineural hearing loss and vestibular symptoms. Treatment includes steroids and a variety of immunosuppressants. Despite adequate treatment, sensorineural hearing loss can be progressive to the point of deafness. In these patients, a cochlear implant (CI) is indicated. We present the case of a 25-year-old male who underwent cochlear implantation in the left ear. After implantation we noticed brisk variations in impedances which were related to application of the previously prescribed tumor necrosis alpha (TNFα) inhibitor adalimumab. OBJECTIVE Can immunomodulatory therapy in AIED patients after CI fitting affect the quality of hearing rehabilitation? MATERIALS AND METHODS We documented impedances and speech intelligibility (Freiburg monosyllable test) of our patient for 1 year in dependence on adalimumab therapy. RESULTS Directly after implantation, impedances were within the normal range. During the further course, impedances started to rise, and recurrent adjustments of the implant were needed. Adalimumab therapy was reinitiated, which resulted in a subsequent reduction of impedances. CONCLUSION Cochlear implantation can be necessary in some AIED patients and poses a sufficient method for hearing rehabilitation. Depending on the activity of the underlying disease, a rise in impedances may occur. Immunomodulatory treatment may therefore be necessary to maintain adequate hearing results with the CI.
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Affiliation(s)
- Maximilian Armstorfer
- Klinik für Hals-Nasen-Ohren-Heilkunde, Universitätsklinikum Salzburg, Müllner Hauptstraße 48, 5020, Salzburg, Österreich.
| | - Lennart Weitgasser
- Klinik für Hals-Nasen-Ohren-Heilkunde, Universitätsklinikum Salzburg, Müllner Hauptstraße 48, 5020, Salzburg, Österreich
| | - Stefan Tschani
- Klinik für Hals-Nasen-Ohren-Heilkunde, Universitätsklinikum Salzburg, Müllner Hauptstraße 48, 5020, Salzburg, Österreich
| | - Sebastian Rösch
- Klinik und Poliklinik für Hals-Nasen-Ohren-Heilkunde, Universitätsklinikum Regensburg, Regensburg, Deutschland
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Mostkowska A, Rousseau G, Raynal NJM. Repurposing of rituximab biosimilars to treat B cell mediated autoimmune diseases. FASEB J 2024; 38:e23536. [PMID: 38470360 DOI: 10.1096/fj.202302259rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 03/13/2024]
Abstract
Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization of its many biosimilars. Currently, rituximab is prescribed worldwide to treat a vast range of autoimmune diseases mediated by B cells. Here, we present a comprehensive overview of rituximab repurposing in 115 autoimmune diseases across 17 medical specialties, sourced from over 1530 publications. Our work highlights the extent of its off-label use and clinical benefits, underlining the success of rituximab repurposing for both common and orphan immune-related diseases. We discuss the scientific mechanism associated with its clinical efficacy and provide additional indications for which rituximab could be investigated. Our study presents rituximab as a flagship example of drug repurposing owing to its central role in targeting cluster of differentiate 20 positive (CD20) B cells in 115 autoimmune diseases.
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Affiliation(s)
- Agata Mostkowska
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Guy Rousseau
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Noël J-M Raynal
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
- Centre de recherche du CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
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Silva VAR, Pauna HF, Lavinsky J, Guimarães GC, Abrahão NM, Massuda ET, Vianna MF, Ikino CMY, Santos VM, Polanski JF, Silva MNLD, Sampaio ALL, Zanini RVR, Lourençone LFM, Denaro MMDC, Calil DB, Chone CT, Castilho AM. Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment. Braz J Otorhinolaryngol 2023; 89:101303. [PMID: 37647735 PMCID: PMC10474207 DOI: 10.1016/j.bjorl.2023.101303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 08/06/2023] [Indexed: 09/01/2023] Open
Abstract
OBJECTIVES To review and provide evidence-based recommendations for the diagnosis and treatment of otosclerosis. METHODS Task force members were educated on knowledge synthesis methods, including electronic database search, review and selection of relevant citations, and critical appraisal of selected studies. Articles written in English or Portuguese on otosclerosis were eligible for inclusion. The American College of Physicians' guideline grading system and the American Thyroid Association's guideline criteria were used for critical appraisal of evidence and recommendations for therapeutic interventions. RESULTS The topics were divided into 2 parts: 1) Diagnosis - audiologic and radiologic; 2) Treatment - hearing AIDS, pharmacological therapy, stapes surgery, and implantable devices - bone-anchored devices, active middle ear implants, and Cochlear Implants (CI). CONCLUSIONS The pathophysiology of otosclerosis has not yet been fully elucidated, but environmental factors and unidentified genes are likely to play a significant role in it. Women with otosclerosis are not at increased risk of worsening clinical condition due to the use of contraceptives or during pregnancy. Drug treatment has shown little benefit. If the patient does not want to undergo stapedotomy, the use of hearing aids is well indicated. Implantable systems should be indicated only in rare cases, and the CI should be indicated in cases of profound deafness.
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Affiliation(s)
- Vagner Antonio Rodrigues Silva
- Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas (FCM), Departamento de Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Campinas, SP, Brazil
| | - Henrique Furlan Pauna
- Hospital Universitário Cajuru, Departamento de Otorrinolaringologia, Curitiba, PR, Brazil
| | - Joel Lavinsky
- Universidade Federal do Rio Grande do Sul (UFRGS), Departamento de Ciências Morfológicas, Porto Alegre, RS, Brazil
| | - Guilherme Corrêa Guimarães
- Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas (FCM), Departamento de Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Campinas, SP, Brazil
| | - Nicolau Moreira Abrahão
- Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas (FCM), Departamento de Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Campinas, SP, Brazil
| | - Eduardo Tanaka Massuda
- Universidade de São Paulo (USP), Faculdade de Medicina de Ribeirão Preto, Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Ribeirão Preto, SP, Brazil
| | - Melissa Ferreira Vianna
- Irmandade Santa Casa de Misericordia de São Paulo, Departamento de Otorrinolaringologia, São Paulo, SP, Brazil
| | - Cláudio Márcio Yudi Ikino
- Universidade Federal de Santa Catarina, Departamento de Cirurgia e Hospital Universitário, Florianópolis, SC, Brazil
| | - Vanessa Mazanek Santos
- Universidade Federal do Paraná, Hospital de Clínicas, Departamento de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Curitiba, PR, Brazil
| | - José Fernando Polanski
- Universidade Federal do Paraná, Hospital de Clínicas, Departamento de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Curitiba, PR, Brazil; Faculdade Evangélica Mackensie do Paraná, Curitiba, PR, Brazil
| | | | - André Luiz Lopes Sampaio
- Universidade de Brasília (UnB), Faculdade de Medicina, Laboratório de Ensino e Pesquisa em Otorrinolaringologia, Brasília, DF, Brazil
| | | | - Luiz Fernando Manzoni Lourençone
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Bauru, SP, Brazil; Universidade de São Paulo, Hospital de Reabilitação de Anomalias Craniofaciais, Bauru, SP, Brazil
| | | | - Daniela Bortoloti Calil
- Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas (FCM), Departamento de Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Campinas, SP, Brazil
| | - Carlos Takahiro Chone
- Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas (FCM), Departamento de Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Campinas, SP, Brazil
| | - Arthur Menino Castilho
- Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas (FCM), Departamento de Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Campinas, SP, Brazil.
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Huang KH, Lin HC, Lin CD, Wu PC. Relapsing autoimmune inner ear disease with significant response to methotrexate and azathioprine combination therapy: A case report and mini literature review. Medicine (Baltimore) 2023; 102:e33889. [PMID: 37335659 PMCID: PMC10256420 DOI: 10.1097/md.0000000000033889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/10/2023] [Indexed: 06/21/2023] Open
Abstract
RATIONALE Autoimmune inner ear disease typically presents with bilateral hearing loss that progresses over weeks or months though its mechanisms are unknown. Corticosteroids are the first-line treatment, but their responses are variable and relapses are frequent. Thus, many experts have sought to replace corticosteroids with immunosuppressive agents. PATIENT CONCERNS A 35-year-old woman experienced a progressive hearing impairment, initially on the left side and later becoming bilateral. Her response to corticosteroid monotherapy was temporary, and there have been two relapse episodes over several months. DIAGNOSES Autoimmune inner ear disease was considered due to evidence of autoimmunity combined with a clinical course of bilateral and recurrent sensorineural hearing loss and a partial response to corticosteroid therapy. INTERVENTIONS The patient received a 3-day mini-pulse of methylprednisolone at 250 mg/d, followed by 12 mg/d maintenance, and concurrently began an azathioprine regimen gradually increasing to 100 mg/day as a corticosteroid-sparing agent. OUTCOMES Three weeks after immunosuppressive therapy, hearing and pure-tone audiometry improved, and after 7 weeks, methylprednisolone was tapered to 8 mg/d. The dosage was further reduced by adding methotrexate at 7.5 mg/week, resulting in a reduction to 4 mg/d as maintenance therapy after 4 weeks. LESSONS For patients who are unresponsive to corticosteroids or experience difficulty tolerating them, a combination therapy of methotrexate and azathioprine is recommended as a viable alternative as this regimen is well-tolerated and yields positive outcomes.
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Affiliation(s)
- Kuan-Hsuan Huang
- Department of Education, Shin Kong Wu Ho Su Memorial Hospital, Taipei, Taiwan
| | - Hsiao-Ching Lin
- Department of Education, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chia-Der Lin
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Otolaryngology Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Po-Chang Wu
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
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Gordis TM, Shah SR, Ward C, Rizk HG. Disease-Modifying Antirheumatic Drugs in the Treatment of Autoimmune Inner Ear Disease: A Systematic Review and Meta-Analysis of Auditory and Vestibular Outcomes. Otol Neurotol 2023; 44:2-9. [PMID: 36509432 DOI: 10.1097/mao.0000000000003743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To answer the following question: In patients with primary autoimmune inner ear disease (AIED), (population) what impact do disease-modifying antirheumatic agents (DMARDs) (intervention) when compared with no treatment or corticosteroids (comparison) have on auditory and vestibular outcomes (outcome)? STUDY DESIGN Systematic review and meta-analysis. DATA SOURCES According to PRISMA guidelines, PubMed, Scopus, CINAHL, and Cochrane Library databases were searched from inception to March 10, 2022. STUDY SELECTION Studies of patients receiving DMARDs for the treatment of AIED were selected for review. Case reports, phase I/II trials, studies of patients with secondary AIED, and studies of AIED patients receiving solely corticosteroids were excluded. DATA EXTRACTION Primary outcomes were pure-tone audiometry and speech discrimination scores at baseline and after DMARD treatment. Secondary outcomes were rates of subjective audiovestibular complaints and rates of adverse reactions. No objective vestibular outcomes underwent meta-analysis. DATA SYNTHESIS Mean differences were calculated using RevMan 5.4. Heterogeneity was assessed with the Q test and I2 statistic. Pooled prevalence rates of audiovestibular symptoms were expressed as a percentage with 95% confidence intervals. RESULTS Ten studies with a total of 187 patients were included. Treatments included methotrexate, etanercept, azathioprine, anakinra, cyclophosphamide, rituximab, and infliximab. Mean treatment duration was 10.8 ± 22.2 months and mean follow-up was 13.7 ± 8.1 months. The pure-tone audiometry and speech discrimination scores mean differences between baseline and post-DMARD were -2.1 [-4.1, -0.1] dB and 13.9 [8.5, 19.4] %, respectively. Seven studies reported 38 adverse events, four of which were classified as serious. CONCLUSION DMARDs showed statistically significant improvement in auditory outcomes, as well as subjective symptoms, with relatively low rates of adverse events. They warrant further exploration to better compare with corticosteroids.
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Affiliation(s)
- Tamar M Gordis
- Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
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Balouch B, Meehan R, Suresh A, Zaheer HA, Jabir AR, Qatanani AM, Suresh V, Kaleem SZ, McKinnon BJ. Use of biologics for treatment of autoimmune inner ear disease. Am J Otolaryngol 2022; 43:103576. [DOI: 10.1016/j.amjoto.2022.103576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/21/2022] [Accepted: 07/31/2022] [Indexed: 11/01/2022]
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Combination Immunosuppressive Therapy in Primary Autoimmune Inner Ear Disease in Pregnancy. Case Rep Otolaryngol 2022; 2022:9210780. [PMID: 35340893 PMCID: PMC8956394 DOI: 10.1155/2022/9210780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/04/2022] [Indexed: 11/17/2022] Open
Abstract
Objective. Autoimmune inner ear disease (AIED) is a rare disorder characterized by rapidly progressive, sensorineural hearing loss that demonstrates good responsiveness to corticosteroid and immunosuppressive therapy. The pathophysiology is likely driven by chronic trafficking of immune cells into the inner ear, targeting inner ear proteins to coordinate inflammation. Suppression or modulation of the immune response can minimize cochleitis allowing for potential recovery of hearing. It is an otologic emergency requiring a multidisciplinary approach to management to commence immunosuppressive therapy. This can be achieved using steroids, immunomodulators, plasmapheresis, intravenous immunoglobulin, or biologic agents. Treatment decisions are further complicated in pregnancy and require supervision by an obstetrician and maternal-fetal medicine (MFM) specialist. Concerns include safe dosing of steroids and potential for transplacental migration of immune complexes. We provide the first comprehensive literature review on AIED and its implications in pregnancy. We frame our discussion in the context of the second reported case of primary AIED in pregnancy and the first to show excellent response to immunosuppressive therapy. Methods. We reviewed the presented case and literature on AIED. Results. A 27-year-old, pregnant, HSP-70 positive woman was diagnosed with AIED and had excellent recovery of hearing and balance following a combination of steroid treatment, augmented by oral immunomodulators, plasmapheresis, and IVIG. Conclusion. AIED is a diagnostic challenge, and treatment considerations are complex when encountered in pregnancy. Management requires multidisciplinary involvement between otolaryngologists, immunologists, and obstetricians to balance maternal and fetal health outcomes.
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Derebery MJ, Christopher L. Allergy, Immunotherapy, and Alternative Treatments for Dizziness. Otolaryngol Clin North Am 2021; 54:1057-1068. [PMID: 34294437 DOI: 10.1016/j.otc.2021.05.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Allergic reactions may result in central symptoms of dizziness, including nonspecific chronic imbalance, Meniere's disease, and autoimmune inner ear disease. Excepting first-generation antihistamines, and short-term use of steroids, most pharmacotherapies used to treat allergic rhinitis have limited benefit in treating allergically induced or related dizziness. Allergy immunotherapy and/or an elimination diet for diagnosed food allergies have been found to be effective treatments. Individuals diagnosed with autoimmune inner ear disease remain challenging to treat and may require high-dose, long-term steroid treatment, biologics, or immunomodulators for symptom control.
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Affiliation(s)
- M Jennifer Derebery
- House Ear Clinic and Institute, 2100 West Third Street, Los Angeles, CA 90057, USA.
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Vambutas A, Davia DV. Biologics for Immune-Mediated Sensorineural Hearing Loss. Otolaryngol Clin North Am 2021; 54:803-813. [PMID: 34119332 DOI: 10.1016/j.otc.2021.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Immune-mediated hearing losses include autoimmune inner ear disease, sudden sensorineural hearing loss, and Meniere's disease. Standard therapy for an acute decline in hearing is timely use of corticosteroids. Although 60% to 70% of patients are initially corticosteroid-responsive, that responsiveness is lost over time. In corticosteroid-resistant patients, increased expression of interleukin (IL)-1 is observed, and these patients may benefit from IL-1 inhibition. Autoinflammatory diseases are characterized by dysregulation of the innate immune response, clinically include sensorineural hearing loss, and benefit from IL-1 inhibition, thereby further establishing the relationship of IL-1 with immune-mediated sensorineural hearing loss.
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Affiliation(s)
- Andrea Vambutas
- Department of Otolaryngology, Zucker School of Medicine at Hofstra-Northwell, Hearing and Speech Center, 430 Lakeville Road, New Hyde Park, NY 11040, USA.
| | - Daniella V Davia
- Department of Otolaryngology, Zucker School of Medicine at Hofstra-Northwell, Hearing and Speech Center, 430 Lakeville Road, New Hyde Park, NY 11040, USA
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Breslin NK, Varadarajan VV, Sobel ES, Haberman RS. Autoimmune inner ear disease: A systematic review of management. Laryngoscope Investig Otolaryngol 2020; 5:1217-1226. [PMID: 33364414 PMCID: PMC7752060 DOI: 10.1002/lio2.508] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/30/2020] [Accepted: 11/17/2020] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVES The study systematically reviewed the existing literature on the management of autoimmune inner ear disease (AIED). STUDY DESIGN Systematic review. METHODS We performed a literature search of Embase, NCBI, Cochrane, and Web of Science databases from April 1990 to April 2020. Inclusion criteria included studies that were retrospective or prospective in nature evaluating the treatment of AIED with audiometric data measuring hearing outcomes during treatment. Hearing improvement was the primary study outcome and improvement in vestibular symptoms was the secondary study outcome. RESULTS Sixteen of 412 candidate articles were included in our study. Systemic steroid treatment is most commonly described. Alternative treatment modalities included intratympanic steroid treatment, methotrexate, cyclophosphamide, azathioprine, infliximab, etanercept, adalimumab, golimumab, methylprednisolone, rituximab, and anakinra. CONCLUSION Systemic corticosteroids are the first line treatment of AIED. Intratympanic steroids are a potential adjuvant or alternative treatment for patients who cannot tolerate or become refractory to steroid treatment. Steroid nonresponders may benefit from biologic therapy. Alternative treatment modalities including nonsteroidal immunosuppressants and biologics have been studied in small cohorts of patients with varying results. Prospective studies investigating the efficacy of biologic and nonsteroidal therapy are warranted. LEVEL OF EVIDENCE 2.
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Affiliation(s)
| | - Varun V. Varadarajan
- Department of Otolaryngology—Head and Neck SurgeryThe Ohio State UniversityColumbusOhioUSA
| | - Eric S. Sobel
- Department of Medicine, Division of Rheumatology and Clinical ImmunologyUniversity of FloridaGainesvilleFloridaUSA
| | - Rex S. Haberman
- Department of Otolaryngology—Head and Neck SurgeryUniversity of FloridaGainesvilleFloridaUSA
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Strum D, Kim S, Shim T, Monfared A. An update on autoimmune inner ear disease: A systematic review of pharmacotherapy. Am J Otolaryngol 2020; 41:102310. [PMID: 31733712 DOI: 10.1016/j.amjoto.2019.102310] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 09/30/2019] [Indexed: 11/28/2022]
Affiliation(s)
- David Strum
- Division of Otolaryngology-Head and Neck Surgery, George Washington University, 2300 M St NW, 4th floor, Washington, DC 20037, United States
| | - Sunny Kim
- Division of Otolaryngology-Head and Neck Surgery, George Washington University, 2300 M St NW, 4th floor, Washington, DC 20037, United States
| | - Timothy Shim
- Division of Otolaryngology-Head and Neck Surgery, George Washington University, 2300 M St NW, 4th floor, Washington, DC 20037, United States
| | - Ashkan Monfared
- Division of Otolaryngology-Head and Neck Surgery, George Washington University, 2300 M St NW, 4th floor, Washington, DC 20037, United States.
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Frye MD, Ryan AF, Kurabi A. Inflammation associated with noise-induced hearing loss. THE JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA 2019; 146:4020. [PMID: 31795714 PMCID: PMC7480080 DOI: 10.1121/1.5132545] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/17/2019] [Accepted: 06/20/2019] [Indexed: 05/22/2023]
Abstract
Inflammation is a complex biological response to harmful stimuli including infection, tissue damage, and toxins. Thus, it is not surprising that cochlear damage by noise includes an inflammatory component. One mechanism by which inflammation is generated by tissue damage is the activation of damage-associated molecular patterns (DAMPs). Many of the cellular receptors for DAMPS, including Toll-like receptors, NOD-like receptors, and DNA receptors, are also receptors for pathogens, and function in the innate immune system. DAMP receptors are known to be expressed by cochlear cells, and binding of molecules released by damaged cells to these receptors result in the activation of cell stress pathways. This leads to the generation of pro-inflammatory cytokines and chemokines that recruit pro-inflammatory leukocytes. Extensive evidence indicates pro-inflammatory cytokines including TNF alpha and interleukin 1 beta, and chemokines including CCL2, are induced in the cochlea after noise exposure. The recruitment of macrophages into the cochlea has also been demonstrated. These provide substrates for noise damage to be enhanced by inflammation. Evidence is provided by the effectiveness of anti-inflammatory drugs in ameliorating noise-induced hearing loss. Involvement of inflammation provides a wide variety of additional anti-inflammatory and pro-resolution agents as potential pharmacological interventions in noise-induced hearing loss.
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Affiliation(s)
- Mitchell D Frye
- Callier Center for Communication Disorders, School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas, Texas 75080, USA
| | - Allen F Ryan
- Department of Surgery/Otolaryngology, University of California San Diego, School of Medicine, and Veterans Administration Medical Center, La Jolla, California 92093, USA
| | - Arwa Kurabi
- Department of Surgery/Otolaryngology, University of California San Diego, School of Medicine, and Veterans Administration Medical Center, La Jolla, California 92093, USA
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Das S, Bakshi SS, Seepana R. Demystifying autoimmune inner ear disease. Eur Arch Otorhinolaryngol 2019; 276:3267-3274. [DOI: 10.1007/s00405-019-05681-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 10/01/2019] [Indexed: 02/06/2023]
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Padoan R, Cazzador D, Pendolino AL, Felicetti M, De Pascalis S, Zanoletti E, Bovo R, Martini A, Schiavon F. Cogan’s syndrome: new therapeutic approaches in the biological era. Expert Opin Biol Ther 2019; 19:781-788. [DOI: 10.1080/14712598.2019.1611779] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Roberto Padoan
- Rheumatology Unit, Department of Medicine DIMED, University of Padova, Padova, Italy
| | - Diego Cazzador
- Otorhinolaryngology Unit, Department of Neurosciences, University of Padova, Padova, Italy
- Section of Human Anatomy, Department of Neuroscience, University of Padova, Padova, Italy
| | - Alfonso Luca Pendolino
- Otorhinolaryngology Unit, Department of Neurosciences, University of Padova, Padova, Italy
| | - Mara Felicetti
- Rheumatology Unit, Department of Medicine DIMED, University of Padova, Padova, Italy
| | - Susanna De Pascalis
- Emergency Unit, Department of Medicine and Surgery, University of Bologna, Bologna, Italy
| | - Elisabetta Zanoletti
- Otorhinolaryngology Unit, Department of Neurosciences, University of Padova, Padova, Italy
| | - Roberto Bovo
- Otorhinolaryngology Unit, Department of Neurosciences, University of Padova, Padova, Italy
| | - Alessandro Martini
- Otorhinolaryngology Unit, Department of Neurosciences, University of Padova, Padova, Italy
| | - Franco Schiavon
- Rheumatology Unit, Department of Medicine DIMED, University of Padova, Padova, Italy
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Sakano H, Harris JP. Emerging options in immune-mediated hearing loss. Laryngoscope Investig Otolaryngol 2018; 4:102-108. [PMID: 30828626 PMCID: PMC6383306 DOI: 10.1002/lio2.205] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 05/27/2018] [Accepted: 07/12/2018] [Indexed: 12/14/2022] Open
Abstract
Objective AIED (autoimmune inner ear disease) is an autoimmune process that leads to the dysfunction of the inner ear, resulting in fluctuating, audiovestibular symptoms. Although the pathogenesis is likely heterogeneous, immune processes within the inner ear ultimately lead to histopathologic changes and sensorineural hearing loss. This review will discuss the latest evidence on treatment options. Methods A literature search on articles pertaining to the treatment of autoimmune inner ear disease was performed on PubMed. Results Corticosteroid treatment continues to remain as first line therapy for AIED but long-term responsiveness is poor. Cytotoxic chemotherapies can be effective alternatives for steroid nonresponsive patients, but significant side effects may limit their use. Intratympanic steroid injections are beneficial and although there is not enough evidence currently to supplant oral steroid trial they may be a useful adjunct if steroid toxicity is an issue. The efficacy of biologic agents has been variable. Compared to placebo, etanercept does not improve the hearing improvement already attained by steroids alone. However, open pilot studies of other biologic agents show hearing improvements, improvements in tinnitus/aural fullness/vertigo, ability to wean steroid dependency, or benefits in steroid-resistant AIED. Conclusion There is currently not enough evidence that alternative treatments supersede the use of initial steroid treatment. Biologic agents and intratympanic steroid injections are relatively well tolerated and should be considered as adjunctive therapy. More studies on the efficacy of various biologics and more studies on the treatment of steroid resistant disease especially after initial benefit are still needed. For those who eventually lose their hearing, cochlear implantation remains as a viable option. Level of Evidence expert opinion.
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Affiliation(s)
- Hitomi Sakano
- Department of Otolaryngology-Head and Neck Surgery University of California, San Diego San Diego California U.S.A
| | - Jeffrey P Harris
- Department of Otolaryngology-Head and Neck Surgery University of California, San Diego San Diego California U.S.A
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Hain TC, Cherchi M, Yacovino DA. Bilateral Vestibular Weakness. Front Neurol 2018; 9:344. [PMID: 29904366 PMCID: PMC5990606 DOI: 10.3389/fneur.2018.00344] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 04/30/2018] [Indexed: 02/02/2023] Open
Abstract
Bilateral vestibular weakness (BVW) is a rare cause of imbalance. Patients with BVW complain of oscillopsia. In approximately half of the patients with BVW, the cause remains undetermined; in the remainder, the most common etiology by far is gentamicin ototoxicity, followed by much rarer entities such as autoimmune inner ear disease, meningitis, bilateral Ménière’s disease, bilateral vestibular neuritis, and bilateral vestibular schwannomas. While a number of bedside tests may raise the suspicion of BVW, the diagnosis should be confirmed by rotatory chair testing. Treatment of BVW is largely supportive. Medications with the unintended effect of vestibular suppression should be avoided.
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Affiliation(s)
- Timothy C Hain
- Department of Otolaryngology, Northwestern University, Chicago, IL, United States.,Department of Physical Therapy and Human Movement Science, Northwestern University, Chicago, IL, United States
| | - Marcello Cherchi
- Department of Neurology, Northwestern University, Chicago, IL, United States
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Rituximab Not Effective for Hearing Loss in Cogan's Syndrome. Case Rep Rheumatol 2016; 2016:8352893. [PMID: 27843668 PMCID: PMC5098068 DOI: 10.1155/2016/8352893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/07/2016] [Indexed: 11/18/2022] Open
Abstract
Importance. Rituximab was not effective in ameliorating the hearing loss in a patient with atypical Cogan's syndrome. Observations. We report the case of a patient who developed acute bilateral uveitis and sensorineural hearing loss. A diagnosis of atypical Cogan's syndrome was made. The patient's hearing loss did not improve despite high dose steroids and azathioprine. Rituximab was administered given a recent report of its efficacy in a patient with refractory disease; however, our patient's hearing loss did not improve. Conclusion. Hearing loss in Cogan's syndrome is difficult to treat. Though rituximab was ineffective in our case, earlier administration in the disease course could be effective for future patients.
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Otologic disorders causing dizziness, including surgery for vestibular disorders. HANDBOOK OF CLINICAL NEUROLOGY 2016; 137:279-93. [PMID: 27638078 DOI: 10.1016/b978-0-444-63437-5.00020-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This chapter will focus on vertigo/dizziness due to inner-ear malformations, labyrinthine fistula, otosclerosis, infectious processes, and autoimmune inner-ear disorders. Inner-ear malformation due to dehiscence of the superior semicircular canal is the most recently described inner-ear malformation. Vertigo/dizziness is typically induced by sound and pressure stimuli and can be associated with auditory symptoms (conductive or mixed hearing loss). Labyrinthine fistula, except after surgery for otosclerosis, in the context of trauma or chronic otitis media with cholesteatoma, still remains a challenging disorder due to multiple uncertainties regarding diagnostic and management strategies. Otosclerosis typically manifests with auditory symptoms and conductive or mixed hearing loss on audiometry. Vertigo/dizziness is rare in nonoperated otosclerosis and should draw clinical attention to an inner-ear malformation. Computed tomography scan confirms otosclerosis in most cases and should rule out an inner-ear malformation, avoiding needless middle-ear surgical exploration. Labyrinth involvement after an infectious process is unilateral when it complicates a middle-ear infection but can be bilateral after meningitis. Labyrinth involvement due to an inflammatory disease is a challenging issue, particularly when restricted to the inner ear. The diagnosis relies on the bilateral and rapid aggravation of audiovestibular symptoms that will not respond to conventional therapy but to immunosuppressive drugs.
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An open label study to evaluate the safety and efficacy of intratympanic golimumab therapy in patients with autoimmune inner ear disease. Otol Neurotol 2015; 35:1515-21. [PMID: 25203561 DOI: 10.1097/mao.0000000000000566] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To evaluate the safety and efficacy of intratympanically injected golimumab (GLM), a TNF-α inhibitor, as a steroid-sparing agent for patients with steroid-dependent autoimmune inner ear disease (AIED). STUDY DESIGN Open label. SETTING Tertiary referral center. PATIENTS Ten patients with steroid-dependent AIED were enrolled in Stage 2. The average patient age at enrollment was 59, with an average of 12.5 years from the start of bilateral hearing loss symptoms. The average dose of daily prednisone at the start of injections was 18 mg. INTERVENTION Intratympanic injection of GLM. MAIN OUTCOME MEASURE Hearing loss progression (treatment failure) was defined as either an increase in pure-tone thresholds by frequency or a decrease in word recognition score. RESULTS There were no serious adverse events. Five of seven per-protocol subjects experienced stable pure-tone thresholds in the injected ear, whereas 4 had stable word recognition scores. Two subjects experienced an improvement in word recognition scores. The results support the hypothesis that GLM may be a promising treatment. CONCLUSIONS The TNF-α inhibitor GLM stabilized hearing in 3 of 7 per-protocol subjects with AIED and allowed a complete tapering off of prednisone in those 7 subjects. Studies with larger samples sizes are warranted.
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Okano T. Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss. Front Pharmacol 2014; 5:205. [PMID: 25228882 PMCID: PMC4151383 DOI: 10.3389/fphar.2014.00205] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 08/16/2014] [Indexed: 12/20/2022] Open
Abstract
Sensorineural hearing loss (SNHL) is a common clinical condition resulting from dysfunction in one or more parts in the auditory pathway between the inner ear and auditory cortex. Despite the prevalence of SNHL, little is known about its etiopathology, although several mechanisms have been postulated including ischemia, viral infection or reactivation, and microtrauma. Immune-mediated inner ear disease has been introduced and accepted as one SNHL pathophysiology; it responds to immunosuppressive therapy and is one of the few reversible forms of bilateral SNHL. The concept of immune-mediated inner ear disease is straightforward and comprehensible, but criteria for clinical diagnosis and the precise mechanism of hearing loss have not been determined. Moreover, the therapeutic mechanisms of corticosteroids are unclear, leading to several misconceptions by both clinicians and investigators concerning corticosteroid therapy. This review addresses our current understanding of the immune system in the inner ear and its involvement in the pathophysiology in SNHL. Treatment of SNHL, including immune-mediated inner ear disorder, will be discussed with a focus on the immune mechanism and immunocompetent cells as therapeutic targets. Finally, possible interventions modulating the immune system in the inner ear to repair the tissue organization and improve hearing in patients with SNHL will be discussed. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL.
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Affiliation(s)
- Takayuki Okano
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University Kyoto, Japan
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Lobo DR, García-Berrocal JR, Ramírez-Camacho R. New prospects in the diagnosis and treatment of immune-mediated inner ear disease. World J Methodol 2014; 4:91-98. [PMID: 25332908 PMCID: PMC4202484 DOI: 10.5662/wjm.v4.i2.91] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/10/2014] [Accepted: 04/11/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune inner ear disease (AIED) represents a very fertile research field and the advancements in the understanding of this disease have a direct application not only in patients affected with this condition but also in other inner ear disorders that share the same injury mechanism, damage to the inner ear hair cells. AIED also presents many challenges that have still to be overcome. Firstly, access to the inner ear is limited, as many interventions such as biopsies can result in great irreversible damage. Secondly, there are no completely specific markers for AIED. Lack of a definitive diagnosis can result in the treatment of patients not affected with the disease and, therefore, no response. Finally, some patients become refractory to glucocorticoids and new therapies are needed. This review offers an overview of the animal models that have contributed to the understanding of AIED pathophysiology, the value of currently available diagnostic tests, and therapeutic options, with a special focus on new therapies for non responders or patients refractory to glucocorticoids. Among these new options for therapy, biological agents have been tested recently, whereas gene and stem cell therapy may have a role in the future. The intratympanic route of administration avoids the systemic side effects associated with currently used drugs, and may become a more frequent approach in the future.
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Matsuoka AJ, Harris JP. Autoimmune inner ear disease: a retrospective review of forty-seven patients. Audiol Neurootol 2013; 18:228-39. [PMID: 23817208 DOI: 10.1159/000351289] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Accepted: 03/29/2013] [Indexed: 01/22/2023] Open
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.
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Affiliation(s)
- Akihiro J Matsuoka
- Department of Otolaryngology - Head and Neck Surgery, Northwestern University, Chicago, IL 60611, USA.
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Mijovic T, Zeitouni A, Colmegna I. Autoimmune sensorineural hearing loss: the otology-rheumatology interface. Rheumatology (Oxford) 2013; 52:780-9. [DOI: 10.1093/rheumatology/ket009] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Perspectives of pharmacological treatment in otosclerosis. Eur Arch Otorhinolaryngol 2012; 270:793-804. [PMID: 22843095 DOI: 10.1007/s00405-012-2126-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 07/17/2012] [Indexed: 12/20/2022]
Abstract
To review our current knowledge of the pathologic bone metabolism in otosclerosis and to discuss the possibilities of non-surgical, pharmacological intervention. Otosclerosis has been suspected to be associated with defective measles virus infection, local inflammation and consecutive bone deterioration in the human otic capsule. In the early stages of otosclerosis, different pharmacological agents may delay the progression or prevent further deterioration of the disease and consecutive hearing loss. Although effective anti-osteoporotic drugs have become available, the use of sodium fluoride and bisphosphonates in otosclerosis has not yet been successful. Bioflavonoids may relieve tinnitus due to otosclerosis, but there is no data available on long-term application and effects on sensorineural hearing loss. In the initial inflammatory phase, corticosteroids or non-steroidal anti-inflammatory drugs may be effective; however, extended systemic application may lead to serious side effects. Vitamin D administration may have effects on the pathological bone loss, as well as on inflammation. No information has been reported on the use of immunosuppressive drugs. Anti-cytokine targeted biological therapy, however, may be feasible. Indeed, one study on the local administration of infliximab has been reported. Potential targets of future therapy may include osteoprotegerin, RANK ligand, cathepsins and also the Wnt-β-catenin pathway. Finally, anti-measles vaccination may delay the progression of the disease and potentially decrease the number of new cases. In conclusion, stapes surgery remains to be widely accepted treatment of conductive hearing loss due to otosclerosis. Due to lack of solid evidence, the place of pharmacological treatment targeting inflammation and bone metabolism needs to be determined by future studies.
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Review of the biologic agents used for immune-mediated inner ear disease. ACTA OTORRINOLARINGOLOGICA ESPANOLA 2012; 64:223-9. [PMID: 22770424 DOI: 10.1016/j.otorri.2012.04.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Revised: 04/19/2012] [Accepted: 04/23/2012] [Indexed: 12/20/2022]
Abstract
INTRODUCTION AND OBJECTIVES Immune-mediated inner ear disease (IMIED) is one of the few reversible forms of sensorineural hearing loss. Treatment is based on high-dose corticosteroids, although long-term therapy is associated with serious adverse effects; this has led to the use of other agents or different routes of administration such as transtympanic delivery. This study analyses the role of biological agents in IMIED management. MATERIAL AND METHODS We searched PUBMED for studies that examined the response to treatment with different biological agents in patients with IMIED. The following data were extracted from the selected studies and entered into a standardised database: exclusion and inclusion criteria, characteristics of the patients studied, treatment, outcome measures and response rates achieved. RESULTS Thirteen studies were included in this review. A TNF alpha inhibitor (etanercept, infliximab, adalimumab) was used in 8 studies, an IL-1 antagonist (anakinra) was used in 3 studies and rituximab, an antibody directed against the CD20 surface antigen on B lymphocytes, was evaluated in 2 studies. Most studies achieved a hearing improvement or stabilisation in more than 70% of treated patients. CONCLUSIONS Biological agents can play a role in the management of patients with IMIED, at least in those patients who do not respond to conventional therapy or whose hearing is not stabilised. However, specially-designed randomised controlled clinical trials are needed to assess their effectiveness.
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Liu YC, Rubin R, Sataloff RT. Treatment-refractory autoimmune sensorineural hearing loss: response to infliximab. EAR, NOSE & THROAT JOURNAL 2011; 90:23-8. [PMID: 21229506 DOI: 10.1177/014556131109000107] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
We conducted a retrospective study to assess the effects of infliximab, a chimeric monoclonal antibody, on hearing in patients with autoimmune sensorineural hearing loss who had previously not responded to steroid therapy and/or treatment with other immunosuppressive drugs such as methotrexate and cyclophosphamide. We reviewed the records of 8 such patients. Our objective measures of outcome were pure-tone averages at 500, 1,000, 2,000, and 3,000 Hz and speech discrimination scores. At the completion of treatment, no patient exhibited a positive response to infliximab therapy by objective measurements, and only 1 patient (12.5%) reported subjective improvement.
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Affiliation(s)
- Yi-Chun Liu
- Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University, Cleveland, OH, USA
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