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Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches
Acta Otorrinolaringol Esp. 2019;70(2):97---104
www.elsevier.es/otorrino
REVIEW ARTICLE
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches夽 José Ferreira Penêda ∗ , Nuno Barros Lima, Francisco Monteiro, Joana Vilela Silva, Rita Gama, Artur Condé Department of Otorhinolaryngology, Centro-Hospitalar Vila Nova de Gaia-Espinho, Vila Nova de Gaia, Portugal Received 4 July 2017; accepted 28 August 2017 Available online 7 March 2018
KEYWORDS Hearing loss, sensorineural; Autoimmune diseases/diagnosis; Autoimmune diseases/therapy; Hereditaryautoinflammatory diseases; Ménière’s disease
Abstract Introduction: Immune Mediated Inner Ear Disease (IMIED) is a rare form of sensorineural bilateral hearing loss, usually progressing in weeks to months and responsive to immunosuppressive treatment. Despite recent advances, there is no consensus on diagnosis and optimal treatment. ® Methods: A review of articles on IMIED from the last 10 years was conducted using PubMed database. Results: IMIED is a rare disease, mostly affecting middle aged women. It may be a primary ear disease or secondary to autoimmune systemic disease. A dual immune response (both cellular and humoral) seems to be involved. Cochlin may be the inner ear protein targeted in this disease. Distinction from other (core common) forms of neurosensory hearing loss is a challenge. Physical examination is mandatory for exclusion of other causes of hearing loss; audiometry identifies characteristic hearing curves. Laboratory and imaging studies are controversial since no diagnostic marker is available. Conclusion: Despite recent research, IMIED diagnosis remains exclusive. Steroids are the mainstay treatment; other therapies need further investigation. For refractory cases, cochlear implantation is an option and with good relative outcome. © 2018 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 The authors reviewed current evidence on IMIED and propose diagnostic stepwise approach as well as review current evidence on treatment options. ∗ Corresponding author. E-mail address: [email protected] (J.F. Penêda).
https://doi.org/10.1016/j.otorri.2017.08.008 2173-5735 0001-6519/© 2018 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
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PALABRAS CLAVE Pérdida auditiva neurosensorial; Enfermedades autoinmunes/diagnóstico; Enfermedades autoinmunes/terapia; Enfermedades hereditariasautoinflamatorias; Enfermedad de Ménière
Enfermedad inmunomediada del oído interno: diagnóstico y enfoques terapéuticos Resumen Introducción: La enfermedad inmunomediada del oído interno (EIMOI) es una forma rara de pérdida auditiva bilateral sensorineural, que progresa generalmente en semanas a meses y responde al tratamiento inmunosupresor. A pesar de los recientes avances, no hay consenso sobre el diagnóstico y el tratamiento óptimo. Métodos: Se realizó una revisión de artículos sobre la EAOI de los últimos 10 a˜ nos utilizando la ® base de datos PubMed . Resultados: La EIMOI es una enfermedad rara que afecta principalmente a las mujeres de 2 a 50 a˜ nos de edad. Puede ser una enfermedad del oído primaria o secundaria a una enfermedad sistémica autoinmune. Parece estar involucrada una respuesta inmune dual (tanto celular como humoral). La coclina parece ser la proteína del oído interno diana en esta enfermedad. La distinción de otras formas de pérdida de audición neurosensorial es un desafío. El examen físico es obligatorio para la exclusión de otras causas de pérdida de la audición; la audiometría identifica curvas características de pérdida de audición. Los estudios de laboratorio y de imágenes son controvertidos, ya que no hay marcador diagnóstico disponible. Conclusión: A pesar de la investigación reciente, el diagnóstico de la EAOI sigue siendo de exclusión. Los esteroides siguen siendo el pilar del tratamiento; otras terapéuticas necesitan más investigación. Para los casos refractarios, la implantación coclear es una opción con buen resultado relativo. © 2018 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Initial descriptions of autoimmune phenomena affecting the inner ear were made by Cogan, who reported a form of interstitial keratitis associated with vertigo, tinnitus, and usually profound deafness.1 Lehnhardt2 and Schiff and Brown3 also published papers suggesting a possible autoimmune inner ear lesion. However, it was McCabe4 who made the first medical description of this disease and coined autoimmune hearing loss as a medical term. Over the past 40 years, several descriptive variants were used, such as Immune Mediated Inner Ear Disease (IMIED), autoimmune inner ear disease, sensorineural autoimmune hypoacusia, autoimmune cochleopathy or cochleovestibular disease immunologically mediated.5---7 IMIED is a form of sensorineural hypoacusia, usually bilateral and asymmetrical, that progresses in weeks-tomonths and has a positive response to immunosuppressive treatment.7---9 It is one of the few forms of sensorineural hearing loss that is potentially reversible.9,10 IMIED is a rare disease accounting for less than 1% of all cases of hypoacusia --- 5---20 cases per 100,000 people/year.5,7 It affects mostly middle aged women10 and can occur as an isolated inner ear disease --- primary, 2/3 of cases --- or secondary to systemic autoimmune disease.7,8 Pathophysiology mechanisms of this disease remain theoretical.5,7,9,11 This is a rare disease and it affects the inner ear, an organ unavailable for in vivo human biopsy9,10 ; therefore most hypothesis are drawn from animal models and its applicability in human cochlea is infrequently demonstrated.8,9,12 Despite a recent paper implied fungal exposure as potential cause for IMIED, the exact trigger and
inflammatory cascade are unknown.13 Both humoral and cellular immune responses seem to be involved; the discussion of this topic is beyond the scope of this paper, but excellent reviews on current knowledge were made by Goodall and Vambutas.5,9 Despite being known for decades, there is no consensus on diagnostic evaluation in suspected cases of IMIED.10,12,14 Moreover, despite recognized importance of steroid therapy, up to a third of affected patients may be unresponsive1,7,8,10,15 ; several other therapies have been attempted in this subset of patients with different rates of success.6,7 Therefore, the authors recognized the need to evaluate available evidence on diagnostic and therapeutic approaches to a rare but potentially devastating form of hearing loss.
Materials and methods Articles relative to autoimmune hearing loss were searched ® in PubMed database. Mesh terms ‘‘hearing loss, sensorineural’’, ‘‘autoimmune disease, diagnostic’’, ‘‘autoimmune disease, therapy’’, ‘‘hereditary-autoinflammatory diseases’’ and ‘‘Meniere disease’’ were used. Articles in English or Portuguese published in the last ten years were considered (265). After abstract processing, 39 articles were included; quoted articles considered relevant for the issue were also included. There are no published guidelines on the matter.
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches
Results and discussion From the authors perspective, IMIED is the most adequate term and thus the one used in this paper. It fits the disease more properly than autoimmune hearing loss because it embraces the vestibular component of this disease and contemplates that only a minority has actual systemic autoimmune disease. Nowadays, IMIED diagnosis is based on typical clinical presentation, exclusion of other (more common) diseases and a positive response to steroids.7,16 The typical patient is a middle aged woman,10 usually complaining of hearing loss progression over weeks to months, affecting one or both ears, with possible fluctuation in severity.4,7,9,10,16 50---80% report vestibular symptoms7,10 likewise making it a cochleovestibular rather than only a cochlear disease. Distinction from other causes of sensorineural hearing loss is, as stated previously, mandatory for accurate diagnosis.7,10 Despite unclear in several cases, progression time seems the major criteria to distinguish IMIED from more common forms of sensorineural hearing loss,7 such as sudden hearing loss and age-related hearing loss; Table 1 summarizes other differences.7,17,18 Meniere’s disease is other important differential diagnosis. In fact, 25---50% of IMIED patients report hearing loss, tinnitus and vertigo, the clinical triad of Meniere.7,10,19 Symptom fluctuation is another common feature of both diseases, justifying the high suspicion index needed for correct diagnosis in early stages of disease.7,19 The fact that some forms of Meniere’s disease seem to have underlying autoimmune phenomena20---25 made some authors to consider IMIED and Meniere’s disease different presentations of the same disease spectrum.16,26,27 Current advances on pathophysiology of Meniere’s disease enlighten that some forms of the disease are immune mediated in a way that allelic variations on innate immune response genes influence disease course20,23---25,28 ; however, due to subject complexity and peripheric connection to IMIED, exhaustive discussion on the matter is beyond the scope of this article. Recently, a heterogeneous group of autoinflammatory diseases has been described. Their baseline pathophysiology is uncontrolled inflammation due to absence or inactivation of several inflammation related proteins (pyrin, cryopyrin, mevalonate kinase or TNF-receptor).29 A subset of this diseases, called Cryopyrin-Associated Periodic Syndrome (CAPS), results in systemic inflammation due to IL-1 release, hearing loss, systemic amyloidosis and skin rashes.5,30 CAPS phenotype encompasses Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and Neonatal-Onset Multisystem Inflammatory Disorder (NOMID, or Chronic Infantile Neurologic, Cutaneous and Articular --- CINCA --- syndrome) as a severity spectrum.30,31 CAPS is inherited in a monogenic autosomal dominant manner and characterized by gain-of-function mutation of NLRP-3 gene; this gene codifies cryopyrin, a protein involved in IL-1 activation.5,30,31 In typical cases, clinical presentation raises suspicion over a specific syndrome which is confirmed by genetic analysis; however, most frequently diagnosis is undermined due to incomplete phenotypic presentation or overlapping characteristics.29,30
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Table 2 compares IMIED to Meniere Disease and Autoinflammatory diseases.5,20,23---25,28,32,33 Full body examination and systematic search for autoimmune signals is crucial to identify up to a third of IMIED patients who have an underlying systemic disease.7,9 However, in IMIED, physical examination is usually clueless and important mainly to exclude other diagnosis: otoscopy is normal, tuning fork tests are consistent with unilateral/bilateral sensorineural hearing loss and, as stated previously, vestibular examination may be altered in a substantial portion of patients.7 The audiogram defines the type and magnitude of the hearing loss.7 Despite no standard guidelines exist, Rauch original definition is still used and requires the presence of bilateral sensorineural hearing loss of 30 dB in at least one frequency, with progression documented in less than 3 months (threshold shift of 15 dB in one frequency, or 10 dB in two contiguous frequencies or significant change in discrimination score).7,34 In some cases of secondary IMIED, a conductive type audiogram may be present7 ; this is due to middle ear effusions in granulomatosis with polyangiitis or relapsing polychondritis, or to incudostapedial joint arthritis in patients affected by rheumatoid arthritis.7 The fact that IMIED may present in several clinical profiles --- sudden repetitive (fluctuating) or rapidly progressive hearing loss (weeks-to-months), unilateral, bilateral or late bilateral after unilateral injury, isolated hearing loss or with Meniere triad (25---50%) --- makes its diagnosis challenging.7,11 Like Meniere’s Disease, most frequently only disease course can proof the diagnosis accurate. Thus, physicians long have searched for a diagnostic gold standard. However, the value of laboratory evaluation in IMIED is controversial since no diagnostic marker is available.6,7,35 Despite great initial expectation on antibodies for Heat Shock Protein 70 (HSP-70) in the early nineties,36,37 further studies did not confirm its utility.14,38 Antibodies for recombinant human CTL2 are under investigation39 and show promising results. After targeted immune lesion of inner ear had been shown to occur through CD4+ cell specific for cochlin,40 further work have confirmed its role in IMIED.41 Some authors even recommend that cochlin antibodies should be routinely tested in patients with suspected IMIED or otherwise unexplained sensorineural hearing loss.12 Meanwhile, several combinations of routine serologic tests have been advocated by most authors,7,10,11 despite scarce evidence supporting them. Its major aim seems to be to exclude alternative diagnosis; but it may be dispensable when systemic autoimmune disease is not suspected, since this studies have no prognostic value.7 From the authors perspective, in the absence of clinical suspicion of other entity, a basic laboratory testing consisting of complete blood count, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-nuclear antibodies, HIV and fluorescent treponemal antibody absorption test is sufficient. Some authors advocate that phenotypic analysis of peripheral blood lymphocytes is mandatory based on the findings of low numbers of CD4+ and CD8+ cells in some forms of sudden hearing loss.42 Patients who respond to steroid therapy tend to normalize lymphocytes levels --- a finding common to other autoimmune diseases --- supporting the theory that this form of IMIED presenting with sudden hearing loss may be considered a form of immunodeficiency.42 A
100 Table 1
J.F. Penêda et al. Causes of sensorineural hearing loss. Sudden HL
IMIED
Age-related HL
Progression Etiology
<72 h Vascular, viral?
Weeks-to-months Autoimmune
Evolution Laterality
Full recovery/stable loss Unilateral
Vestibular symptoms Systemic disease association
Rare
Fluctuation/further loss Bilateral asymmetric (unilateral complain 50%) 50---80%
Years Vascular, metabolic? Slowly progressive Bilateral symmetric
Cardiovascular risk factors in elderly; viral infection in youngsters
Systemic autoimmune disease (1/3)
Eventually ---
HL: hearing loss; IMIED: Immune-Mediated Inner-Ear Disease.
Table 2
Genetics and citokine expression of IMIED. Disease
Genetics SS
a
SR
a
IMIED
Meniere’s disease
Autoinflammatory CAPS diseases
FCAS MWS NOMID Monarch-1 H Syndrome
[adaptive, T-cell and auto-antibody mediated autoimmune response]
[innate, monocytic mediated autoinflammatory response] TLR10 MIF SEMA3D IL-1 DPT MICA PRKCB NFKB1 NLRP3 (AD)
Citokyne expression TNF␣ INFϒ IL-17 IL-1
IL-1 IL-1 IL-1
NLRP12 (AD) SLC29A3 (AR)
SS: steroid sensitive AIED; AIED: autoimmune inner-ear disease; SR AIED: steroid resistant AIED; CAPS: Cryopyrin-Associated Periodic Syndrome; FCAS: Familial Cold Autoinflammatory Syndrome; MWS: Muckle-Wells Syndrome; NOMID: Neonatal-Onset Multisystem Inflammatory Disease; TNF ␣: Tumor Necrosis Factor ␣; INFϒ: Interferon ϒ; IL-17: Interleukin 17; AD: autosomal dominant; IL-1B: Interleukin 1; AR: Autosomal Recessive; MIF: Macrophage Migration Inhibitory Factor; MICA: Major histocompatibility complex class I chain related A; NFKB1: Nuclear Factor Kappa B Subunit 1; TLR10: Toll-Like Receptor 10; SEMA2D: Semaphorin 3D; DPT: Dermatopontin; NLRP3: NACHT, LRR and PYD domains-containing protein 3; NLRP12: NLR Family Pyrin Domain Containing 12; SLC29A3: Solute Carrier Family 29 Member 3; PRKCB: Protein Kinase C Beta. a Immunological pattern more prevalent in each type of IMIED; shown between [] and under GENETICS topic for better layout.
list of major and minor criteria including peripheral blood lymphocytes analysis were proposed to diagnose IMIED.11,42 Likewise imaging studies (MRI, PET scan) are needed to exclude other pathologies, such as acoustic neuroma or distant metastasis.7,11 Cochlear enhancement in MRI, interpreted as surrogate for inner ear inflammation due to immune complex deposition and hematolabyrinthic barrier rupture is described by some authors43 --- however, the authors recognized that evidence is insufficient to recommend MRI as initial generalized evaluation. Therefore, from the authors point of view, and despite growing interest in cochlin antibodies detection, IMIED diagnosis still relies on the three-step approach consisting in a typical clinical presentation, exclusion of other causes and a positive response to immunosuppressive therapy.
Systemic steroid therapy have been recognized for long as a surrogate for immunosuppressive therapy in IMIED, ever since McCabe works in the late eighties.4 In fact, systemic steroids are the only universally accepted treatment for IMIED and invariably the initial step in drug therapy.7,8 They seem to have a dual action, not only acting as antiinflammatory agents but also as sodium balance regulators. However, there is no consensus regarding administration dosage, frequency or treatment duration.6---8 Most authors describe variations of Rauch’s treatment Scheme,34 consisting of an initial course of high dose systemic steroids --- prednisone 1 mg/kg/day, maximum 60 mg/day --- for 4 weeks, followed by slow weaning (8 weeks) till a maintenance dose of 10---20 mg/day. To complete the initial 4 weeks of treatment, with or without audiogram evaluation at 2 weeks, seems to be beneficial, even in apparent early
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches non-responders (no change in threshold after 2 weeks), a fact pointed out by Rauch in his visionary work.34 The fact is that some patients are late-responders and show hearing recovery only after a month of therapy.7,8,34 Nowadays, maintenance dose is aimed at the lowest dose compatible with stable hearing.8 Rauch reported a response rate to systemic steroids of 50---70%34 ; more recent works are consistent with his findings.44 There is no consensus about response definition, but the criteria used by Broughton44 seem adequate --- >10 dB in Pure Tone Average (PTA) or >12% in discrimination score. Unresponsive patients after initial 4-week treatment course may be quickly weaned --- 12 days.7,34 Besides the fact that up to a third of affected patients show no benefit with steroid therapy, most studies agree that, as in most autoimmune diseases, steroid sensitivity tends to decline over time --- in long term courses, only a minority remains responsive (14% at 34 months).8,9,44 Systemic steroids recognized side effects, which affect 15% of patients and lead to a 6% treatment discontinuation
Table 3
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rate,45 further point out the need for additional treatment options. Several drugs have been tried as second-line or adjunctive therapy in IMIED; cyclophosphamide, part of initial McCabe’s treatment,4 was abandoned due to reported toxicity7 ; several reports of intratympanic steroids benefit justify its usage46---48 ; different cytokine expression in steroid-resistant IMIED reasoned anakinra trials with promising results.49---51 IL-1 a recognized mediator not in only in corticoid-resistant forms of IMIED, but also in autoinflammatory diseases associated with hearing loss, were IL-1  antagonism is a useful therapeutic weapon.5,30,35 In spite of not representing mainstay of therapy in corticoid resistant IMIED, IL-1 reduction seems to correlate with hearing improvement5 which justifies anakinra usage in this group of patients. Besides, a recent study found significant association between IL-1 polymorphisms and susceptibility for both Meniere disease and sudden hearing loss,33 a fact that further sustains the overlap among IMIED and other forms of sensorineural hearing loss.
Alternative drug therapy in IMIED.
Drug
Body of evidence
Summary
Intratympanic steroids
Silverstein (1996): SRT improvement in 4/5 patients; PTA unchanged Parnes (1999): report of success in 1 patient Garcia-Berrocal (2006): symptomatic response in 4/8 patients with refractory IMIED Harris (2013): hearing improvement in 3 patients; adjunctive therapy McCabe (1979): synergistic effect Lasak (2001): benefit in discrimination scores, 17 patients Broughton (2004): 1/6 patients improved Buniel (2009), Mijovic (2013): concerns on toxicity Di Leo (2011): report of hearing normalization in 1 patient after 1-year treatment Broughton (2004): limited response Hautefort (2009): 1 patient with Cogan syndrome Broughton (2004): limited response Saracaydin (1993): hearing improvement in 10/12 patients Salley (2001) --- overall improvement in 35/50 patients Matteson (2001) --- hearing improvement in 11/17 patients Harris (2003): no benefit over placebo; 67 patients Street (2006): possible benefit in association with TNF-␣ inhibition Rahman (2001): stabilization or improvement in 11/12 patients Matteson (2005): improvement in 10/23 patient Cohen (2005): no better than placebo, 20 patients Liu (2011): no benefit in 8 patients Heywood (2013): success in 1 patient with steroid-resistant IMIED Van Wijk (2006): benefit in 7/9 patients Vergles (2010): good outcome in 1 patient with RA Conway (2011): IMIED de novo in 2 patients Vambutas (2014): hearing improvement in 7/10 with steroid-resistant IMIED Cohen (2011): hearing improvement in 5/7 patients Luetje (1997): improved or stable hearing in 8/16 patients
Probable benefit
Cyclophosphamide
Cyclosporin A Mycophenolate mofetil (MMF) Azatioprine (AZA) Metotrexate (MTX)
Etanercept (anti-TNF␣)
Infliximab (anti-TNF␣)
Intratympanic infliximab Adalimumab (anti-TNF␣) Anakinra (anti-IL1) Rituximab (anti-CD20) Plasmapheresis
Scarce benefit concerns on toxicity
Insufficient evidence Insufficient evidence Insufficient evidence Benefit not confirmed
Benefit not confirmed
No benefit
Insufficient evidence Concerns about IMIED de novo Probable benefit in steroid-resistant IMIED Insufficient evidence Insufficient evidence
IMIED: Immune-Mediated Inner-Ear Disease; PTA: Pure-Tone Average; TNF␣: Tumor Necrosis Factor ␣; IL1: InterLeukin 1-.
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Anamnesis
J.F. Penêda et al. Timing: weeks-to-months (rapidly progressive OR sudden repetitive OR fluctuating) Cochleovestibular symptoms: tinnitus, vertigo, aural fullness Systemic autoimmune involvement: uveitis, nephritis, pneumonitis, bowel disorder, skin rash
Conflict of interests None declared.
Physical examination
Normal otoscopy Tuning fork test: sensorineural hearing loss unilateral/bilateral suspected
Sensorineural asymmetric bilateral hearing loss- confirmed
References
Audiometr y
Laboratory studies
MRI
Exclude other forms of sensorineural hearing loss Diagnose unknow systemic autoimmune disease CBC, CRP, ESR, ANA, RF, HIV, FRAA Eventually phenotypic analysisi of peripheral blood lymphocytes
Exclude retrocochlear / CNS pathology: acoustic neurinoma, MS, metastasis, stroke Eventually identify hematolabyrinthic barrier rupture due to immunocomplexes deposition
Figure 1 Diagnostic approach. CBC: complete blood count; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; ANA: anti-nuclear antibody; RF: rheumatoid factor; HIV: human immunodeficiency virus; FTAA: fluorescent treponemal antibody absorption test; CNS: central nervous system; MS: multiple sclerosis.
Table 3 sums up current evidence regarding alternative immunosuppressive therapy.4,7,8,15,44,46---49,52-67 All IMIED patients demand a monthly audiogram evaluation until hearing stabilization and, due to the higher rates of relapse, follow-up audiogram every 6 months.7,68,69 Hearing aids are indicated when hearing loss is symptomatic and do not reverse with medical therapy; cochlear implantation is reserved for profound irreversible bilateral hearing loss.7 In IMIED, cochlear implantation is associated with better outcome than in other forms of sensorineural hearing loss.7,70
Conclusion IMIED is a form of sensorineural bilateral hearing loss that progresses in a period of weeks to months. There is no diagnostic marker for the disease, despite recent advances in anti-cochlin antibodies detection. Therefore, it remains a diagnosis of exclusion, based on clinical presentation and response to treatment. Considerable overlap with other forms of sensorineural hearing loss is likely (sudden hearing loss, Meniere’s disease, auto-inflammatory syndromes). Systemic steroids are the only therapy with strong supporting evidence. Intratympanic steroid administration may have a role as adjunctive therapy; IL-1 antagonists are a promising weapon in patients with steroid-resistant IMIED. Further studies are needed to evaluate other treatments. Cochlear implantation is the end-of-the-line treatment with particularly good outcome in IMIED patients. The authors propose a stepwise diagnostic approach (Fig. 1) and sum up current evidence regarding treatment options.
Funding None declared.
1. Cogan D. Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms. Arch Ophthalmol. 1945;33:144---9. 2. Lehnhardt E. Sudden hearing disorders occurring simultaneously or successively on both sides. Z Laryngol Rhinol Otol. 1958;37:1---16. 3. Schiff N, Brown D. Hormones and sudden deafness. Laryngoscope. 1974;84:1959---81. 4. McCabe B. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol. 1979;88:585---9. 5. Vambutas A, Pathak S. AAO: Autoimmune and Autoinflammatory (Disease) in Otology: what is new in immune-mediated hearing loss. Laryngoscope Investig Otolaryngol. 2016;1:110---5. 6. Dayal V, Ellman M, Sweiss N. Autoimmune inner ear disease: clinical and laboratory findings and treatment outcome. J Otolaryngol --- Head Neck Surg. 2008;37:591---6. 7. Mijovic T, Zeitouni A, Colmegna I. Autoimmune sensorineural hearing loss: the otology---rheumatology interface. Rheumatology. 2013;52:780---9. 8. Buniel M, Geelan-Hansen K, Weber P, Tuohy V. Immunosuppressive therapy for autoimmune inner ear disease. Immunotherapy. 2009;1:425---34. 9. Goodall A, Siddiq M. Current understanding of the pathogenesis of autoimmune inner ear disease: a review. Clin Otolaryngol. 2015;40:412---9. 10. Branco M, Caroc ¸a C, Campelo P, Tinoco C, Cac ¸ador M, Pac ¸o J. Autoimmune inner ear disease: literature review. Gaz Médica. 2016;3:22---6. 11. Lobo D, García-Berrocal J, Ramírez-Camacho R. New prospects in the diagnosis and treatment of immune-mediated inner ear disease. World J Methodol. 2014;4:91---8. 12. Baruah P. Cochlin in autoimmune inner ear disease: is the search for an inner ear autoantigen over? Auris Nasus Larynx. 2014;41:499---501. 13. Pathak S, Hatam LJ, Bonagura V, Vambutas A. Innate immune recognition of molds and homology to the inner ear protein, cochlin, in patients with autoimmune inner ear disease. J Clin Immunol. 2013;33:1204---5. 14. Ianuale C, Cadoni G, De Feo E, Liberati L, Simo RK, Paludetti G, et al. A systematic review and meta-analysis of the diagnostic accuracy of anti-heat shock protein 70 antibodies for the detection of autoimmune hearing loss. Otol Neurotol. 2013;34:214---9. 15. Harris D, Mikulec A, Carls S. Autoimmune inner ear disease preliminary case report: audiometric findings following steroid treatments. Am J Audiol. 2013;22:120---4. 16. Suchan M, Kaliarik L, Krempaska S, Koval J. Immune-mediated cochleovestibular disease. Bratisl Med J. 2016;117:87---90. 17. Stachler R, Chandrasekhar S, Archer S, Rosenfeld RM, Schwartz RS, Barrs DM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg. 2012;146:1---35. 18. Roth T. Aging of the auditory system. Handb Clin Neurol. 2015;129:357---73. 19. Espinosa-Sanchez J, Lopez-Escamez J. Menière’s disease. Handb Clin Neurol. 2016;137:257---77. 20. Cabrera S, Sanchez E, Requena T, Martinez-Bueno M, Benitez J, Peres N, et al. Intronic variants in the NFKB1 gene may influence hearing forecast in patients with unilateral sensorineural hearing loss in meniere’s disease. PLOS ONE. 2014;9:1---8. 21. Frejo L, Martin-Sanz E, Teggi R, Trinidad G, Soto-Varela A, Santos-Perez S, et al. Extended phenotype and clinical sub-
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches
22.
23.
24.
25.
26.
27. 28.
29.
30.
31.
32.
33.
34. 35.
36.
37.
38.
39.
groups in unilateral Meniere disease: a cross-sectional study with cluster analysis. Clin Otolaryngol. 2017:1---9. Frejo L, Soto-Varela A, Santos-Perez S, Aran I, Batuecas-Caletrio A, Perez-Guillen V, et al. Clinical subgroups in bilateral meniere disease. Front Neurol. 2016;7:1---10. Gazquez I, Moreno A, Aran I, Soto-Varela A, Santos S, Perez Guarriges H, et al. MICA-STR A.4 is associated with slower hearing loss progression in patients with Ménière’s disease. Otol Neurotol. 2012;33:223---9. Martín-Sierra C, Gallego-Martinez A, Requena T, Frejo L, Batuecas-Caletrío A, Lopez-Escamez JA. Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere’s disease. Eur J Hum Gen. 2017;25:200---7. Martín-Sierra C, Requena T, Frejo L, Price SD, Gallego-Martinez A, Batuecas-Caletrio A, et al. A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere’s disease. Hum Mol Gen. 2016;25:3407---15. Gazquez I, Soto-Varela A, Aran I, Santos S, Batuecas A, Trinidad G, et al. High prevalence of systemic autoimmune diseases in patients with Meniere’s disease. PLoS ONE. 2011;6:1---7. Bovo R, Ciorba A, Martini A. Vertigo and autoimmunity. Eur Arch Otorhinolaryngol. 2010;267:13---9. Requena T, Gazquez I, Moreno A, Batuecas A, Aran I, SotoVArela A, et al. Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere’s disease. Immunogenetics. 2013;65:345---55. De Pieri C, Vuch J, De Martino E, Bianco AM, Ronfani L, Athanasakis E, et al. Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study. Pediatr Rheumatol Online J. 2015;13:1---8. Kuemmerle-Deschner J, Verma D, Endres T, Broderick L, de Jesus AA, Hofer F, et al. Clinical and molecular phenotypes of low-penetrance variants in NLRP3: diagnostic and therapeutic challenges. Arthritis Rheumatol. 2017. Martorana D, Bonatti F, Mozzoni P, Vaglio A, Percesepe A. Monogenic autoinflammatory diseases with mendelian inheritance: genes, mutations, and genotype/phenotype correlations. Front Immunol. 2017;8:1---17. Yazdani N, Khorsandi Ashtiani MT, Zarandy MM, Mohammadi SJ, Ghazavi H, Mahrampour E, et al. Association between MIF gene variation and meniere’s disease. Int J Immunogenet. 2013;40:488---91. Furuta T, Teranishi M, Uchida Y, Nishio N, Kato K, Otake H, et al. Association of interleukin-1 gene polymorphisms with sudden sensorineural hearing loss and Ménière’s disease. Int J Immunogenet. 2011;38:249---54. Rauch S. Clinical management of immune-mediated inner-ear disease. Ann N Y Acad Sci. 1997;830:203---10. Vambutas A, DeVoti J, Goldofsky E, Gordon M, Lesser M, Bonagura V. Alternate splicing of interleukin-1 receptor type II (IL1R2) in vitro correlates with clinical glucocorticoid responsiveness in patients with AIED. PLoS ONE. 2009;4:1---9. Harris J, Sharp P. Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss. Laryngoscope. 1990;100:516---24. Bloch D, San Martin J, Rauch S, Moscicki R, Bloch K. Serum antibodies to heat shock protein 70 in sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 1995;121:1167---71. Yeom K, Gray J, Nair T, Arts HA, Telian SA, Disher MJ, et al. Antibodies to HSP-70 in normal donors and autoimmune hearing loss patients. Laryngoscope. 2003;113:1770---6. Kommareddi P, Nair T, Vallurupalli M, Telian SA, Arts HA, El-Kashlan HK, et al. Autoantibodies to recombinant human CTL2 in autoimmune hearing loss. Laryngoscope. 2009; 119:924---32.
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40. Solares C, Edling A, Johnson J, Baek MJ, Hirose K, Huges GB, et al. Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides. J Clin Invest. 2004;113:1210---7. 41. Baek M, Park H, Johnson J, Altuntas CZ, Jane-Wit D, Jaini R, et al. Increased frequencies of cochlin-specific T cells in patients with autoimmune sensorineural hearing loss. J Immunol. 2006;177:4203---10. 42. García Berrocal JR, Ramírez-Camacho R. Sudden sensorineural hearing loss: supporting the immunologic theory. Ann Otol Rhinol Laryngol. 2002;111:989---97. 43. Okano T. Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss. Front Pharmacol. 2014;5:1---8. 44. Broughton S, Meyerhoff W, Cohen S. Immune-mediated inner ear disease: 10-Year experience. Semin Arthritis Rheum. 2004;34:544---8. 45. Alexander T, Weisman M, Derebery J, Espeland MA, Gantz BJ, Gulya AJ, et al. Safety of high-dose corticosteroids for the treatment of autoimmune inner ear disease. Otol Neurotol. 2009;30:443---8. 46. Silverstein H, Choo D, Rosenberg S, Kuhn J, Seidman M, Stein I. Intratympanic steroid treatment of inner ear disease and tinnitus (preliminary report). Ear Nose Throat J. 1996;75:468---71. 47. Parnes L, Sun A, Freeman D. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope. 1999;109:1---17. 48. García-Berrocal J, Ibᘠnez A, Rodríguez A, González-García JA, Verdaguer JM, Trinidad A, et al. Alternatives to systemic steroid therapy for refractory immune-mediated inner ear disease: a physiopathologic approach. Eur Arch Otorhinolaryngol. 2006;263:977---82. 49. Vambutas A, Lesser M, Mullooly V, Pathak S, Zahtz G, Rosen L, et al. Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease. J Clin Invest. 2014;124:4115---22. 50. Svrakic M, Pathak S, Goldofsky E, Hoffman R, Chandrasekhar SS, Sperling N, et al. Diagnostic and prognostic utility of measuring tumor necrosis factor in the peripheral circulation of patients with immune-mediated sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 2012;138:1052---8. 51. Pathak S, Goldofsky E, Vivas E, Bonagura V, Vambutas A. IL1 is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease. J Immunol. 2011;186:1870---9. 52. Lasak J, Sataloff R, Hawkshaw M, Carey T, Lyons K, Spiegel J. Autoimmune inner ear disease: steroid and cytotoxic drug therapy. Ear Nose Throat J. 2001;80, 808---11, 815---6. 53. Di Leo E, Coppola F, Nettis E, Vacca A, Quaranta N. Late recovery with cyclosporine-A of an auto-immune sudden sensorineural hearing loss. Acta Otorhinolaryngol Ital. 2011;31:399---401. 54. Hautefort C, Loundon N, Montchilova M, Marlin S, Garabedian E, Ulinski T. Mycophenolate mofetil as a treatment of steroid dependent Cogan’s syndrome in childhood. Int J Pediatr Otorhinolaryngol. 2009;73:1477---9. 55. Saracaydin A, Katircioglu S, Karatay M. Azathioprine in combination with steroids in the treatment of autoimmune inner-ear disease. J Int Med Res. 1993;21:192---6. 56. Salley L, Grimm M, Sismanis A, Spencer R, Wise C. Methotrexate in the management of immune mediated cochleovesitibular disorders: clinical experience with 53 patients. J Rheumatol. 2001;28:1037---40. 57. Matteson E, Fabry D, Facer G, Beatty CW, Driscoll CL, Strome SE, et al. Open trial of methotrexate as treatment for autoimmune hearing loss. Arthritis Rheum. 2001;45:146---50. 58. Harris J, Weisman M, Derebery J, Espeland MA, Gantz BJ, Gulya AJ, et al. Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial. JAMA. 2003;290:1875---83.
104 59. Street I, Jobanputra P, Proops DW. Etanercept, a tumour necrosis factor alpha receptor antagonist, and methotrexate in acute sensorineural hearing loss. J Laryngol Otol. 2006; 120:1064---6. 60. Rahman M, Poe D, Choi H. Etanercept therapy for immunemediated cochleovestibular disorders: preliminary results in a pilot study. Otol Neurotol. 2001;22:619---24. 61. Cohen S, Shoup A, Weisman M, Harris J. Etanercept treatment for autoimmune inner ear disease: results of a pilot placebocontrolled study. Otol Neurotol. 2005;26:903---7. 62. Heywood R, Hadavi S, Donnelly S, Patel N. Infliximab for autoimmune inner ear disease: case report and literature review. J Laryngol Otol. 2013;127:1145---7. 63. Liu Y, Rubin R, Sataloff R. Treatment-refractory autoimmune sensorineural hearing loss: response to infliximab. Ear Nose Throat J. 2011;90:23---8. 64. Van Wijk F, Staecker H, Keithley E, Lefebvre P. Local perfusion of the tumor necrosis factor ␣ blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol Neurootol. 2006;11:357---65.
J.F. Penêda et al. 65. Vergles J, Radic M, Kovacic J. The journal of rheumatology successful use of adalimumab for treating rheumatoid arthritis with autoimmune sensorineural hearing loss: two birds with one stone. J Rheumatol. 2010;37:37---9. 66. Conway R, Khan S, Foley-Nolan D. Use of adalimumab in treatment of autoimmune sensorineural hearing loss: a word of caution. J Rheumatol. 2011;38:176. 67. Luetje C, Berliner K. Plasmapheresis in autoimmune inner ear disease: long-term follow-up. Am J Otol. 1997;18:572---6. 68. Zeitoun H, Beckman J, Arts HA, Lansford CD, Lee DS, El-Kashlan HK, et al. Corticosteroid response and supporting cell antibody in autoimmune hearing loss. Arch Otolaryngol Head Neck Surg. 2005;131:665---72. 69. Niparko J, Wang N, Rauch S, Russel GB, Espeland MA, Pierce JJ, et al. Serial audiometry in a clinical trial of AIED treatment. Otol Neurotol. 2005;26:908---17. 70. Wang J, Yuen H, Shipp D, Stewart S, Lyn VYW, Chen JM, et al. Cochlear implantation in patients with autoimmune inner ear disease including Cogan syndrome: a comparison with age- and sex-matched controls. Laryngoscope. 2010;120:2478---83.
www.elsevier.es/otorrino
REVIEW ARTICLE
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches夽 José Ferreira Penêda ∗ , Nuno Barros Lima, Francisco Monteiro, Joana Vilela Silva, Rita Gama, Artur Condé Department of Otorhinolaryngology, Centro-Hospitalar Vila Nova de Gaia-Espinho, Vila Nova de Gaia, Portugal Received 4 July 2017; accepted 28 August 2017 Available online 7 March 2018
KEYWORDS Hearing loss, sensorineural; Autoimmune diseases/diagnosis; Autoimmune diseases/therapy; Hereditaryautoinflammatory diseases; Ménière’s disease
Abstract Introduction: Immune Mediated Inner Ear Disease (IMIED) is a rare form of sensorineural bilateral hearing loss, usually progressing in weeks to months and responsive to immunosuppressive treatment. Despite recent advances, there is no consensus on diagnosis and optimal treatment. ® Methods: A review of articles on IMIED from the last 10 years was conducted using PubMed database. Results: IMIED is a rare disease, mostly affecting middle aged women. It may be a primary ear disease or secondary to autoimmune systemic disease. A dual immune response (both cellular and humoral) seems to be involved. Cochlin may be the inner ear protein targeted in this disease. Distinction from other (core common) forms of neurosensory hearing loss is a challenge. Physical examination is mandatory for exclusion of other causes of hearing loss; audiometry identifies characteristic hearing curves. Laboratory and imaging studies are controversial since no diagnostic marker is available. Conclusion: Despite recent research, IMIED diagnosis remains exclusive. Steroids are the mainstay treatment; other therapies need further investigation. For refractory cases, cochlear implantation is an option and with good relative outcome. © 2018 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 The authors reviewed current evidence on IMIED and propose diagnostic stepwise approach as well as review current evidence on treatment options. ∗ Corresponding author. E-mail address: [email protected] (J.F. Penêda).
https://doi.org/10.1016/j.otorri.2017.08.008 2173-5735 0001-6519/© 2018 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
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J.F. Penêda et al.
PALABRAS CLAVE Pérdida auditiva neurosensorial; Enfermedades autoinmunes/diagnóstico; Enfermedades autoinmunes/terapia; Enfermedades hereditariasautoinflamatorias; Enfermedad de Ménière
Enfermedad inmunomediada del oído interno: diagnóstico y enfoques terapéuticos Resumen Introducción: La enfermedad inmunomediada del oído interno (EIMOI) es una forma rara de pérdida auditiva bilateral sensorineural, que progresa generalmente en semanas a meses y responde al tratamiento inmunosupresor. A pesar de los recientes avances, no hay consenso sobre el diagnóstico y el tratamiento óptimo. Métodos: Se realizó una revisión de artículos sobre la EAOI de los últimos 10 a˜ nos utilizando la ® base de datos PubMed . Resultados: La EIMOI es una enfermedad rara que afecta principalmente a las mujeres de 2 a 50 a˜ nos de edad. Puede ser una enfermedad del oído primaria o secundaria a una enfermedad sistémica autoinmune. Parece estar involucrada una respuesta inmune dual (tanto celular como humoral). La coclina parece ser la proteína del oído interno diana en esta enfermedad. La distinción de otras formas de pérdida de audición neurosensorial es un desafío. El examen físico es obligatorio para la exclusión de otras causas de pérdida de la audición; la audiometría identifica curvas características de pérdida de audición. Los estudios de laboratorio y de imágenes son controvertidos, ya que no hay marcador diagnóstico disponible. Conclusión: A pesar de la investigación reciente, el diagnóstico de la EAOI sigue siendo de exclusión. Los esteroides siguen siendo el pilar del tratamiento; otras terapéuticas necesitan más investigación. Para los casos refractarios, la implantación coclear es una opción con buen resultado relativo. © 2018 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Initial descriptions of autoimmune phenomena affecting the inner ear were made by Cogan, who reported a form of interstitial keratitis associated with vertigo, tinnitus, and usually profound deafness.1 Lehnhardt2 and Schiff and Brown3 also published papers suggesting a possible autoimmune inner ear lesion. However, it was McCabe4 who made the first medical description of this disease and coined autoimmune hearing loss as a medical term. Over the past 40 years, several descriptive variants were used, such as Immune Mediated Inner Ear Disease (IMIED), autoimmune inner ear disease, sensorineural autoimmune hypoacusia, autoimmune cochleopathy or cochleovestibular disease immunologically mediated.5---7 IMIED is a form of sensorineural hypoacusia, usually bilateral and asymmetrical, that progresses in weeks-tomonths and has a positive response to immunosuppressive treatment.7---9 It is one of the few forms of sensorineural hearing loss that is potentially reversible.9,10 IMIED is a rare disease accounting for less than 1% of all cases of hypoacusia --- 5---20 cases per 100,000 people/year.5,7 It affects mostly middle aged women10 and can occur as an isolated inner ear disease --- primary, 2/3 of cases --- or secondary to systemic autoimmune disease.7,8 Pathophysiology mechanisms of this disease remain theoretical.5,7,9,11 This is a rare disease and it affects the inner ear, an organ unavailable for in vivo human biopsy9,10 ; therefore most hypothesis are drawn from animal models and its applicability in human cochlea is infrequently demonstrated.8,9,12 Despite a recent paper implied fungal exposure as potential cause for IMIED, the exact trigger and
inflammatory cascade are unknown.13 Both humoral and cellular immune responses seem to be involved; the discussion of this topic is beyond the scope of this paper, but excellent reviews on current knowledge were made by Goodall and Vambutas.5,9 Despite being known for decades, there is no consensus on diagnostic evaluation in suspected cases of IMIED.10,12,14 Moreover, despite recognized importance of steroid therapy, up to a third of affected patients may be unresponsive1,7,8,10,15 ; several other therapies have been attempted in this subset of patients with different rates of success.6,7 Therefore, the authors recognized the need to evaluate available evidence on diagnostic and therapeutic approaches to a rare but potentially devastating form of hearing loss.
Materials and methods Articles relative to autoimmune hearing loss were searched ® in PubMed database. Mesh terms ‘‘hearing loss, sensorineural’’, ‘‘autoimmune disease, diagnostic’’, ‘‘autoimmune disease, therapy’’, ‘‘hereditary-autoinflammatory diseases’’ and ‘‘Meniere disease’’ were used. Articles in English or Portuguese published in the last ten years were considered (265). After abstract processing, 39 articles were included; quoted articles considered relevant for the issue were also included. There are no published guidelines on the matter.
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches
Results and discussion From the authors perspective, IMIED is the most adequate term and thus the one used in this paper. It fits the disease more properly than autoimmune hearing loss because it embraces the vestibular component of this disease and contemplates that only a minority has actual systemic autoimmune disease. Nowadays, IMIED diagnosis is based on typical clinical presentation, exclusion of other (more common) diseases and a positive response to steroids.7,16 The typical patient is a middle aged woman,10 usually complaining of hearing loss progression over weeks to months, affecting one or both ears, with possible fluctuation in severity.4,7,9,10,16 50---80% report vestibular symptoms7,10 likewise making it a cochleovestibular rather than only a cochlear disease. Distinction from other causes of sensorineural hearing loss is, as stated previously, mandatory for accurate diagnosis.7,10 Despite unclear in several cases, progression time seems the major criteria to distinguish IMIED from more common forms of sensorineural hearing loss,7 such as sudden hearing loss and age-related hearing loss; Table 1 summarizes other differences.7,17,18 Meniere’s disease is other important differential diagnosis. In fact, 25---50% of IMIED patients report hearing loss, tinnitus and vertigo, the clinical triad of Meniere.7,10,19 Symptom fluctuation is another common feature of both diseases, justifying the high suspicion index needed for correct diagnosis in early stages of disease.7,19 The fact that some forms of Meniere’s disease seem to have underlying autoimmune phenomena20---25 made some authors to consider IMIED and Meniere’s disease different presentations of the same disease spectrum.16,26,27 Current advances on pathophysiology of Meniere’s disease enlighten that some forms of the disease are immune mediated in a way that allelic variations on innate immune response genes influence disease course20,23---25,28 ; however, due to subject complexity and peripheric connection to IMIED, exhaustive discussion on the matter is beyond the scope of this article. Recently, a heterogeneous group of autoinflammatory diseases has been described. Their baseline pathophysiology is uncontrolled inflammation due to absence or inactivation of several inflammation related proteins (pyrin, cryopyrin, mevalonate kinase or TNF-receptor).29 A subset of this diseases, called Cryopyrin-Associated Periodic Syndrome (CAPS), results in systemic inflammation due to IL-1 release, hearing loss, systemic amyloidosis and skin rashes.5,30 CAPS phenotype encompasses Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and Neonatal-Onset Multisystem Inflammatory Disorder (NOMID, or Chronic Infantile Neurologic, Cutaneous and Articular --- CINCA --- syndrome) as a severity spectrum.30,31 CAPS is inherited in a monogenic autosomal dominant manner and characterized by gain-of-function mutation of NLRP-3 gene; this gene codifies cryopyrin, a protein involved in IL-1 activation.5,30,31 In typical cases, clinical presentation raises suspicion over a specific syndrome which is confirmed by genetic analysis; however, most frequently diagnosis is undermined due to incomplete phenotypic presentation or overlapping characteristics.29,30
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Table 2 compares IMIED to Meniere Disease and Autoinflammatory diseases.5,20,23---25,28,32,33 Full body examination and systematic search for autoimmune signals is crucial to identify up to a third of IMIED patients who have an underlying systemic disease.7,9 However, in IMIED, physical examination is usually clueless and important mainly to exclude other diagnosis: otoscopy is normal, tuning fork tests are consistent with unilateral/bilateral sensorineural hearing loss and, as stated previously, vestibular examination may be altered in a substantial portion of patients.7 The audiogram defines the type and magnitude of the hearing loss.7 Despite no standard guidelines exist, Rauch original definition is still used and requires the presence of bilateral sensorineural hearing loss of 30 dB in at least one frequency, with progression documented in less than 3 months (threshold shift of 15 dB in one frequency, or 10 dB in two contiguous frequencies or significant change in discrimination score).7,34 In some cases of secondary IMIED, a conductive type audiogram may be present7 ; this is due to middle ear effusions in granulomatosis with polyangiitis or relapsing polychondritis, or to incudostapedial joint arthritis in patients affected by rheumatoid arthritis.7 The fact that IMIED may present in several clinical profiles --- sudden repetitive (fluctuating) or rapidly progressive hearing loss (weeks-to-months), unilateral, bilateral or late bilateral after unilateral injury, isolated hearing loss or with Meniere triad (25---50%) --- makes its diagnosis challenging.7,11 Like Meniere’s Disease, most frequently only disease course can proof the diagnosis accurate. Thus, physicians long have searched for a diagnostic gold standard. However, the value of laboratory evaluation in IMIED is controversial since no diagnostic marker is available.6,7,35 Despite great initial expectation on antibodies for Heat Shock Protein 70 (HSP-70) in the early nineties,36,37 further studies did not confirm its utility.14,38 Antibodies for recombinant human CTL2 are under investigation39 and show promising results. After targeted immune lesion of inner ear had been shown to occur through CD4+ cell specific for cochlin,40 further work have confirmed its role in IMIED.41 Some authors even recommend that cochlin antibodies should be routinely tested in patients with suspected IMIED or otherwise unexplained sensorineural hearing loss.12 Meanwhile, several combinations of routine serologic tests have been advocated by most authors,7,10,11 despite scarce evidence supporting them. Its major aim seems to be to exclude alternative diagnosis; but it may be dispensable when systemic autoimmune disease is not suspected, since this studies have no prognostic value.7 From the authors perspective, in the absence of clinical suspicion of other entity, a basic laboratory testing consisting of complete blood count, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-nuclear antibodies, HIV and fluorescent treponemal antibody absorption test is sufficient. Some authors advocate that phenotypic analysis of peripheral blood lymphocytes is mandatory based on the findings of low numbers of CD4+ and CD8+ cells in some forms of sudden hearing loss.42 Patients who respond to steroid therapy tend to normalize lymphocytes levels --- a finding common to other autoimmune diseases --- supporting the theory that this form of IMIED presenting with sudden hearing loss may be considered a form of immunodeficiency.42 A
100 Table 1
J.F. Penêda et al. Causes of sensorineural hearing loss. Sudden HL
IMIED
Age-related HL
Progression Etiology
<72 h Vascular, viral?
Weeks-to-months Autoimmune
Evolution Laterality
Full recovery/stable loss Unilateral
Vestibular symptoms Systemic disease association
Rare
Fluctuation/further loss Bilateral asymmetric (unilateral complain 50%) 50---80%
Years Vascular, metabolic? Slowly progressive Bilateral symmetric
Cardiovascular risk factors in elderly; viral infection in youngsters
Systemic autoimmune disease (1/3)
Eventually ---
HL: hearing loss; IMIED: Immune-Mediated Inner-Ear Disease.
Table 2
Genetics and citokine expression of IMIED. Disease
Genetics SS
a
SR
a
IMIED
Meniere’s disease
Autoinflammatory CAPS diseases
FCAS MWS NOMID Monarch-1 H Syndrome
[adaptive, T-cell and auto-antibody mediated autoimmune response]
[innate, monocytic mediated autoinflammatory response] TLR10 MIF SEMA3D IL-1 DPT MICA PRKCB NFKB1 NLRP3 (AD)
Citokyne expression TNF␣ INFϒ IL-17 IL-1
IL-1 IL-1 IL-1
NLRP12 (AD) SLC29A3 (AR)
SS: steroid sensitive AIED; AIED: autoimmune inner-ear disease; SR AIED: steroid resistant AIED; CAPS: Cryopyrin-Associated Periodic Syndrome; FCAS: Familial Cold Autoinflammatory Syndrome; MWS: Muckle-Wells Syndrome; NOMID: Neonatal-Onset Multisystem Inflammatory Disease; TNF ␣: Tumor Necrosis Factor ␣; INFϒ: Interferon ϒ; IL-17: Interleukin 17; AD: autosomal dominant; IL-1B: Interleukin 1; AR: Autosomal Recessive; MIF: Macrophage Migration Inhibitory Factor; MICA: Major histocompatibility complex class I chain related A; NFKB1: Nuclear Factor Kappa B Subunit 1; TLR10: Toll-Like Receptor 10; SEMA2D: Semaphorin 3D; DPT: Dermatopontin; NLRP3: NACHT, LRR and PYD domains-containing protein 3; NLRP12: NLR Family Pyrin Domain Containing 12; SLC29A3: Solute Carrier Family 29 Member 3; PRKCB: Protein Kinase C Beta. a Immunological pattern more prevalent in each type of IMIED; shown between [] and under GENETICS topic for better layout.
list of major and minor criteria including peripheral blood lymphocytes analysis were proposed to diagnose IMIED.11,42 Likewise imaging studies (MRI, PET scan) are needed to exclude other pathologies, such as acoustic neuroma or distant metastasis.7,11 Cochlear enhancement in MRI, interpreted as surrogate for inner ear inflammation due to immune complex deposition and hematolabyrinthic barrier rupture is described by some authors43 --- however, the authors recognized that evidence is insufficient to recommend MRI as initial generalized evaluation. Therefore, from the authors point of view, and despite growing interest in cochlin antibodies detection, IMIED diagnosis still relies on the three-step approach consisting in a typical clinical presentation, exclusion of other causes and a positive response to immunosuppressive therapy.
Systemic steroid therapy have been recognized for long as a surrogate for immunosuppressive therapy in IMIED, ever since McCabe works in the late eighties.4 In fact, systemic steroids are the only universally accepted treatment for IMIED and invariably the initial step in drug therapy.7,8 They seem to have a dual action, not only acting as antiinflammatory agents but also as sodium balance regulators. However, there is no consensus regarding administration dosage, frequency or treatment duration.6---8 Most authors describe variations of Rauch’s treatment Scheme,34 consisting of an initial course of high dose systemic steroids --- prednisone 1 mg/kg/day, maximum 60 mg/day --- for 4 weeks, followed by slow weaning (8 weeks) till a maintenance dose of 10---20 mg/day. To complete the initial 4 weeks of treatment, with or without audiogram evaluation at 2 weeks, seems to be beneficial, even in apparent early
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches non-responders (no change in threshold after 2 weeks), a fact pointed out by Rauch in his visionary work.34 The fact is that some patients are late-responders and show hearing recovery only after a month of therapy.7,8,34 Nowadays, maintenance dose is aimed at the lowest dose compatible with stable hearing.8 Rauch reported a response rate to systemic steroids of 50---70%34 ; more recent works are consistent with his findings.44 There is no consensus about response definition, but the criteria used by Broughton44 seem adequate --- >10 dB in Pure Tone Average (PTA) or >12% in discrimination score. Unresponsive patients after initial 4-week treatment course may be quickly weaned --- 12 days.7,34 Besides the fact that up to a third of affected patients show no benefit with steroid therapy, most studies agree that, as in most autoimmune diseases, steroid sensitivity tends to decline over time --- in long term courses, only a minority remains responsive (14% at 34 months).8,9,44 Systemic steroids recognized side effects, which affect 15% of patients and lead to a 6% treatment discontinuation
Table 3
101
rate,45 further point out the need for additional treatment options. Several drugs have been tried as second-line or adjunctive therapy in IMIED; cyclophosphamide, part of initial McCabe’s treatment,4 was abandoned due to reported toxicity7 ; several reports of intratympanic steroids benefit justify its usage46---48 ; different cytokine expression in steroid-resistant IMIED reasoned anakinra trials with promising results.49---51 IL-1 a recognized mediator not in only in corticoid-resistant forms of IMIED, but also in autoinflammatory diseases associated with hearing loss, were IL-1  antagonism is a useful therapeutic weapon.5,30,35 In spite of not representing mainstay of therapy in corticoid resistant IMIED, IL-1 reduction seems to correlate with hearing improvement5 which justifies anakinra usage in this group of patients. Besides, a recent study found significant association between IL-1 polymorphisms and susceptibility for both Meniere disease and sudden hearing loss,33 a fact that further sustains the overlap among IMIED and other forms of sensorineural hearing loss.
Alternative drug therapy in IMIED.
Drug
Body of evidence
Summary
Intratympanic steroids
Silverstein (1996): SRT improvement in 4/5 patients; PTA unchanged Parnes (1999): report of success in 1 patient Garcia-Berrocal (2006): symptomatic response in 4/8 patients with refractory IMIED Harris (2013): hearing improvement in 3 patients; adjunctive therapy McCabe (1979): synergistic effect Lasak (2001): benefit in discrimination scores, 17 patients Broughton (2004): 1/6 patients improved Buniel (2009), Mijovic (2013): concerns on toxicity Di Leo (2011): report of hearing normalization in 1 patient after 1-year treatment Broughton (2004): limited response Hautefort (2009): 1 patient with Cogan syndrome Broughton (2004): limited response Saracaydin (1993): hearing improvement in 10/12 patients Salley (2001) --- overall improvement in 35/50 patients Matteson (2001) --- hearing improvement in 11/17 patients Harris (2003): no benefit over placebo; 67 patients Street (2006): possible benefit in association with TNF-␣ inhibition Rahman (2001): stabilization or improvement in 11/12 patients Matteson (2005): improvement in 10/23 patient Cohen (2005): no better than placebo, 20 patients Liu (2011): no benefit in 8 patients Heywood (2013): success in 1 patient with steroid-resistant IMIED Van Wijk (2006): benefit in 7/9 patients Vergles (2010): good outcome in 1 patient with RA Conway (2011): IMIED de novo in 2 patients Vambutas (2014): hearing improvement in 7/10 with steroid-resistant IMIED Cohen (2011): hearing improvement in 5/7 patients Luetje (1997): improved or stable hearing in 8/16 patients
Probable benefit
Cyclophosphamide
Cyclosporin A Mycophenolate mofetil (MMF) Azatioprine (AZA) Metotrexate (MTX)
Etanercept (anti-TNF␣)
Infliximab (anti-TNF␣)
Intratympanic infliximab Adalimumab (anti-TNF␣) Anakinra (anti-IL1) Rituximab (anti-CD20) Plasmapheresis
Scarce benefit concerns on toxicity
Insufficient evidence Insufficient evidence Insufficient evidence Benefit not confirmed
Benefit not confirmed
No benefit
Insufficient evidence Concerns about IMIED de novo Probable benefit in steroid-resistant IMIED Insufficient evidence Insufficient evidence
IMIED: Immune-Mediated Inner-Ear Disease; PTA: Pure-Tone Average; TNF␣: Tumor Necrosis Factor ␣; IL1: InterLeukin 1-.
102
Anamnesis
J.F. Penêda et al. Timing: weeks-to-months (rapidly progressive OR sudden repetitive OR fluctuating) Cochleovestibular symptoms: tinnitus, vertigo, aural fullness Systemic autoimmune involvement: uveitis, nephritis, pneumonitis, bowel disorder, skin rash
Conflict of interests None declared.
Physical examination
Normal otoscopy Tuning fork test: sensorineural hearing loss unilateral/bilateral suspected
Sensorineural asymmetric bilateral hearing loss- confirmed
References
Audiometr y
Laboratory studies
MRI
Exclude other forms of sensorineural hearing loss Diagnose unknow systemic autoimmune disease CBC, CRP, ESR, ANA, RF, HIV, FRAA Eventually phenotypic analysisi of peripheral blood lymphocytes
Exclude retrocochlear / CNS pathology: acoustic neurinoma, MS, metastasis, stroke Eventually identify hematolabyrinthic barrier rupture due to immunocomplexes deposition
Figure 1 Diagnostic approach. CBC: complete blood count; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; ANA: anti-nuclear antibody; RF: rheumatoid factor; HIV: human immunodeficiency virus; FTAA: fluorescent treponemal antibody absorption test; CNS: central nervous system; MS: multiple sclerosis.
Table 3 sums up current evidence regarding alternative immunosuppressive therapy.4,7,8,15,44,46---49,52-67 All IMIED patients demand a monthly audiogram evaluation until hearing stabilization and, due to the higher rates of relapse, follow-up audiogram every 6 months.7,68,69 Hearing aids are indicated when hearing loss is symptomatic and do not reverse with medical therapy; cochlear implantation is reserved for profound irreversible bilateral hearing loss.7 In IMIED, cochlear implantation is associated with better outcome than in other forms of sensorineural hearing loss.7,70
Conclusion IMIED is a form of sensorineural bilateral hearing loss that progresses in a period of weeks to months. There is no diagnostic marker for the disease, despite recent advances in anti-cochlin antibodies detection. Therefore, it remains a diagnosis of exclusion, based on clinical presentation and response to treatment. Considerable overlap with other forms of sensorineural hearing loss is likely (sudden hearing loss, Meniere’s disease, auto-inflammatory syndromes). Systemic steroids are the only therapy with strong supporting evidence. Intratympanic steroid administration may have a role as adjunctive therapy; IL-1 antagonists are a promising weapon in patients with steroid-resistant IMIED. Further studies are needed to evaluate other treatments. Cochlear implantation is the end-of-the-line treatment with particularly good outcome in IMIED patients. The authors propose a stepwise diagnostic approach (Fig. 1) and sum up current evidence regarding treatment options.
Funding None declared.
1. Cogan D. Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms. Arch Ophthalmol. 1945;33:144---9. 2. Lehnhardt E. Sudden hearing disorders occurring simultaneously or successively on both sides. Z Laryngol Rhinol Otol. 1958;37:1---16. 3. Schiff N, Brown D. Hormones and sudden deafness. Laryngoscope. 1974;84:1959---81. 4. McCabe B. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol. 1979;88:585---9. 5. Vambutas A, Pathak S. AAO: Autoimmune and Autoinflammatory (Disease) in Otology: what is new in immune-mediated hearing loss. Laryngoscope Investig Otolaryngol. 2016;1:110---5. 6. Dayal V, Ellman M, Sweiss N. Autoimmune inner ear disease: clinical and laboratory findings and treatment outcome. J Otolaryngol --- Head Neck Surg. 2008;37:591---6. 7. Mijovic T, Zeitouni A, Colmegna I. Autoimmune sensorineural hearing loss: the otology---rheumatology interface. Rheumatology. 2013;52:780---9. 8. Buniel M, Geelan-Hansen K, Weber P, Tuohy V. Immunosuppressive therapy for autoimmune inner ear disease. Immunotherapy. 2009;1:425---34. 9. Goodall A, Siddiq M. Current understanding of the pathogenesis of autoimmune inner ear disease: a review. Clin Otolaryngol. 2015;40:412---9. 10. Branco M, Caroc ¸a C, Campelo P, Tinoco C, Cac ¸ador M, Pac ¸o J. Autoimmune inner ear disease: literature review. Gaz Médica. 2016;3:22---6. 11. Lobo D, García-Berrocal J, Ramírez-Camacho R. New prospects in the diagnosis and treatment of immune-mediated inner ear disease. World J Methodol. 2014;4:91---8. 12. Baruah P. Cochlin in autoimmune inner ear disease: is the search for an inner ear autoantigen over? Auris Nasus Larynx. 2014;41:499---501. 13. Pathak S, Hatam LJ, Bonagura V, Vambutas A. Innate immune recognition of molds and homology to the inner ear protein, cochlin, in patients with autoimmune inner ear disease. J Clin Immunol. 2013;33:1204---5. 14. Ianuale C, Cadoni G, De Feo E, Liberati L, Simo RK, Paludetti G, et al. A systematic review and meta-analysis of the diagnostic accuracy of anti-heat shock protein 70 antibodies for the detection of autoimmune hearing loss. Otol Neurotol. 2013;34:214---9. 15. Harris D, Mikulec A, Carls S. Autoimmune inner ear disease preliminary case report: audiometric findings following steroid treatments. Am J Audiol. 2013;22:120---4. 16. Suchan M, Kaliarik L, Krempaska S, Koval J. Immune-mediated cochleovestibular disease. Bratisl Med J. 2016;117:87---90. 17. Stachler R, Chandrasekhar S, Archer S, Rosenfeld RM, Schwartz RS, Barrs DM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg. 2012;146:1---35. 18. Roth T. Aging of the auditory system. Handb Clin Neurol. 2015;129:357---73. 19. Espinosa-Sanchez J, Lopez-Escamez J. Menière’s disease. Handb Clin Neurol. 2016;137:257---77. 20. Cabrera S, Sanchez E, Requena T, Martinez-Bueno M, Benitez J, Peres N, et al. Intronic variants in the NFKB1 gene may influence hearing forecast in patients with unilateral sensorineural hearing loss in meniere’s disease. PLOS ONE. 2014;9:1---8. 21. Frejo L, Martin-Sanz E, Teggi R, Trinidad G, Soto-Varela A, Santos-Perez S, et al. Extended phenotype and clinical sub-
Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches
22.
23.
24.
25.
26.
27. 28.
29.
30.
31.
32.
33.
34. 35.
36.
37.
38.
39.
groups in unilateral Meniere disease: a cross-sectional study with cluster analysis. Clin Otolaryngol. 2017:1---9. Frejo L, Soto-Varela A, Santos-Perez S, Aran I, Batuecas-Caletrio A, Perez-Guillen V, et al. Clinical subgroups in bilateral meniere disease. Front Neurol. 2016;7:1---10. Gazquez I, Moreno A, Aran I, Soto-Varela A, Santos S, Perez Guarriges H, et al. MICA-STR A.4 is associated with slower hearing loss progression in patients with Ménière’s disease. Otol Neurotol. 2012;33:223---9. Martín-Sierra C, Gallego-Martinez A, Requena T, Frejo L, Batuecas-Caletrío A, Lopez-Escamez JA. Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere’s disease. Eur J Hum Gen. 2017;25:200---7. Martín-Sierra C, Requena T, Frejo L, Price SD, Gallego-Martinez A, Batuecas-Caletrio A, et al. A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere’s disease. Hum Mol Gen. 2016;25:3407---15. Gazquez I, Soto-Varela A, Aran I, Santos S, Batuecas A, Trinidad G, et al. High prevalence of systemic autoimmune diseases in patients with Meniere’s disease. PLoS ONE. 2011;6:1---7. Bovo R, Ciorba A, Martini A. Vertigo and autoimmunity. Eur Arch Otorhinolaryngol. 2010;267:13---9. Requena T, Gazquez I, Moreno A, Batuecas A, Aran I, SotoVArela A, et al. Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere’s disease. Immunogenetics. 2013;65:345---55. De Pieri C, Vuch J, De Martino E, Bianco AM, Ronfani L, Athanasakis E, et al. Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study. Pediatr Rheumatol Online J. 2015;13:1---8. Kuemmerle-Deschner J, Verma D, Endres T, Broderick L, de Jesus AA, Hofer F, et al. Clinical and molecular phenotypes of low-penetrance variants in NLRP3: diagnostic and therapeutic challenges. Arthritis Rheumatol. 2017. Martorana D, Bonatti F, Mozzoni P, Vaglio A, Percesepe A. Monogenic autoinflammatory diseases with mendelian inheritance: genes, mutations, and genotype/phenotype correlations. Front Immunol. 2017;8:1---17. Yazdani N, Khorsandi Ashtiani MT, Zarandy MM, Mohammadi SJ, Ghazavi H, Mahrampour E, et al. Association between MIF gene variation and meniere’s disease. Int J Immunogenet. 2013;40:488---91. Furuta T, Teranishi M, Uchida Y, Nishio N, Kato K, Otake H, et al. Association of interleukin-1 gene polymorphisms with sudden sensorineural hearing loss and Ménière’s disease. Int J Immunogenet. 2011;38:249---54. Rauch S. Clinical management of immune-mediated inner-ear disease. Ann N Y Acad Sci. 1997;830:203---10. Vambutas A, DeVoti J, Goldofsky E, Gordon M, Lesser M, Bonagura V. Alternate splicing of interleukin-1 receptor type II (IL1R2) in vitro correlates with clinical glucocorticoid responsiveness in patients with AIED. PLoS ONE. 2009;4:1---9. Harris J, Sharp P. Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss. Laryngoscope. 1990;100:516---24. Bloch D, San Martin J, Rauch S, Moscicki R, Bloch K. Serum antibodies to heat shock protein 70 in sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 1995;121:1167---71. Yeom K, Gray J, Nair T, Arts HA, Telian SA, Disher MJ, et al. Antibodies to HSP-70 in normal donors and autoimmune hearing loss patients. Laryngoscope. 2003;113:1770---6. Kommareddi P, Nair T, Vallurupalli M, Telian SA, Arts HA, El-Kashlan HK, et al. Autoantibodies to recombinant human CTL2 in autoimmune hearing loss. Laryngoscope. 2009; 119:924---32.
103
40. Solares C, Edling A, Johnson J, Baek MJ, Hirose K, Huges GB, et al. Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides. J Clin Invest. 2004;113:1210---7. 41. Baek M, Park H, Johnson J, Altuntas CZ, Jane-Wit D, Jaini R, et al. Increased frequencies of cochlin-specific T cells in patients with autoimmune sensorineural hearing loss. J Immunol. 2006;177:4203---10. 42. García Berrocal JR, Ramírez-Camacho R. Sudden sensorineural hearing loss: supporting the immunologic theory. Ann Otol Rhinol Laryngol. 2002;111:989---97. 43. Okano T. Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss. Front Pharmacol. 2014;5:1---8. 44. Broughton S, Meyerhoff W, Cohen S. Immune-mediated inner ear disease: 10-Year experience. Semin Arthritis Rheum. 2004;34:544---8. 45. Alexander T, Weisman M, Derebery J, Espeland MA, Gantz BJ, Gulya AJ, et al. Safety of high-dose corticosteroids for the treatment of autoimmune inner ear disease. Otol Neurotol. 2009;30:443---8. 46. Silverstein H, Choo D, Rosenberg S, Kuhn J, Seidman M, Stein I. Intratympanic steroid treatment of inner ear disease and tinnitus (preliminary report). Ear Nose Throat J. 1996;75:468---71. 47. Parnes L, Sun A, Freeman D. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope. 1999;109:1---17. 48. García-Berrocal J, Ibᘠnez A, Rodríguez A, González-García JA, Verdaguer JM, Trinidad A, et al. Alternatives to systemic steroid therapy for refractory immune-mediated inner ear disease: a physiopathologic approach. Eur Arch Otorhinolaryngol. 2006;263:977---82. 49. Vambutas A, Lesser M, Mullooly V, Pathak S, Zahtz G, Rosen L, et al. Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease. J Clin Invest. 2014;124:4115---22. 50. Svrakic M, Pathak S, Goldofsky E, Hoffman R, Chandrasekhar SS, Sperling N, et al. Diagnostic and prognostic utility of measuring tumor necrosis factor in the peripheral circulation of patients with immune-mediated sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 2012;138:1052---8. 51. Pathak S, Goldofsky E, Vivas E, Bonagura V, Vambutas A. IL1 is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease. J Immunol. 2011;186:1870---9. 52. Lasak J, Sataloff R, Hawkshaw M, Carey T, Lyons K, Spiegel J. Autoimmune inner ear disease: steroid and cytotoxic drug therapy. Ear Nose Throat J. 2001;80, 808---11, 815---6. 53. Di Leo E, Coppola F, Nettis E, Vacca A, Quaranta N. Late recovery with cyclosporine-A of an auto-immune sudden sensorineural hearing loss. Acta Otorhinolaryngol Ital. 2011;31:399---401. 54. Hautefort C, Loundon N, Montchilova M, Marlin S, Garabedian E, Ulinski T. Mycophenolate mofetil as a treatment of steroid dependent Cogan’s syndrome in childhood. Int J Pediatr Otorhinolaryngol. 2009;73:1477---9. 55. Saracaydin A, Katircioglu S, Karatay M. Azathioprine in combination with steroids in the treatment of autoimmune inner-ear disease. J Int Med Res. 1993;21:192---6. 56. Salley L, Grimm M, Sismanis A, Spencer R, Wise C. Methotrexate in the management of immune mediated cochleovesitibular disorders: clinical experience with 53 patients. J Rheumatol. 2001;28:1037---40. 57. Matteson E, Fabry D, Facer G, Beatty CW, Driscoll CL, Strome SE, et al. Open trial of methotrexate as treatment for autoimmune hearing loss. Arthritis Rheum. 2001;45:146---50. 58. Harris J, Weisman M, Derebery J, Espeland MA, Gantz BJ, Gulya AJ, et al. Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial. JAMA. 2003;290:1875---83.
104 59. Street I, Jobanputra P, Proops DW. Etanercept, a tumour necrosis factor alpha receptor antagonist, and methotrexate in acute sensorineural hearing loss. J Laryngol Otol. 2006; 120:1064---6. 60. Rahman M, Poe D, Choi H. Etanercept therapy for immunemediated cochleovestibular disorders: preliminary results in a pilot study. Otol Neurotol. 2001;22:619---24. 61. Cohen S, Shoup A, Weisman M, Harris J. Etanercept treatment for autoimmune inner ear disease: results of a pilot placebocontrolled study. Otol Neurotol. 2005;26:903---7. 62. Heywood R, Hadavi S, Donnelly S, Patel N. Infliximab for autoimmune inner ear disease: case report and literature review. J Laryngol Otol. 2013;127:1145---7. 63. Liu Y, Rubin R, Sataloff R. Treatment-refractory autoimmune sensorineural hearing loss: response to infliximab. Ear Nose Throat J. 2011;90:23---8. 64. Van Wijk F, Staecker H, Keithley E, Lefebvre P. Local perfusion of the tumor necrosis factor ␣ blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol Neurootol. 2006;11:357---65.
J.F. Penêda et al. 65. Vergles J, Radic M, Kovacic J. The journal of rheumatology successful use of adalimumab for treating rheumatoid arthritis with autoimmune sensorineural hearing loss: two birds with one stone. J Rheumatol. 2010;37:37---9. 66. Conway R, Khan S, Foley-Nolan D. Use of adalimumab in treatment of autoimmune sensorineural hearing loss: a word of caution. J Rheumatol. 2011;38:176. 67. Luetje C, Berliner K. Plasmapheresis in autoimmune inner ear disease: long-term follow-up. Am J Otol. 1997;18:572---6. 68. Zeitoun H, Beckman J, Arts HA, Lansford CD, Lee DS, El-Kashlan HK, et al. Corticosteroid response and supporting cell antibody in autoimmune hearing loss. Arch Otolaryngol Head Neck Surg. 2005;131:665---72. 69. Niparko J, Wang N, Rauch S, Russel GB, Espeland MA, Pierce JJ, et al. Serial audiometry in a clinical trial of AIED treatment. Otol Neurotol. 2005;26:908---17. 70. Wang J, Yuen H, Shipp D, Stewart S, Lyn VYW, Chen JM, et al. Cochlear implantation in patients with autoimmune inner ear disease including Cogan syndrome: a comparison with age- and sex-matched controls. Laryngoscope. 2010;120:2478---83.