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Document downloaded from http://www.elsevier.es, day 06/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Acta Otorrinolaringol Esp. 2013;64(3):223---229 www.elsevier.es/otorrino REVIEW ARTICLE Review of the Biological Agents Used for Immune-Mediated Inner Ear Disease夽 David Lobo,a,∗ José R. García-Berrocal,b Almudena Trinidad,b José M. Verdaguer,a Rafael Ramírez-Camachob a b Servicio de Otorrinolaringología, Hospital El Escorial, Universidad Francisco de Vitoria, San Lorenzo de El Escorial, Madrid, Spain Servicio de Otorrinolaringología, Hospital Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, Spain Received 26 February 2012; accepted 23 April 2012 KEYWORDS Immune-mediated inner ear disease; Biological agents; Etanercept; Tumour necrosis factor ␣; Anakinra; Rituximab 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, and 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. © 2012 Elsevier España, S.L. All rights reserved. 夽 Please cite this article as: Lobo David, et al. Revisión de las terapias biológicas en la enfermedad inmunomediada del oído interno. Otorrinolaringol Esp. 2012. http://dx.doi.org/10.1016/j.otorri.2012.04.008. ∗ Corresponding author. E-mail address: [email protected] (D. Lobo). 2173-5735/$ – see front matter © 2012 Elsevier España, S.L. All rights reserved. Document downloaded from http://www.elsevier.es, day 06/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. 224 PALABRAS CLAVE Enfermedad inmunomediada del oído interno; Terapias biológicas; Etanercept; Factor de necrosis tumoral ␣; Anakinra; Rituximab D. Lobo et al. Revisión de las terapias biológicas en la enfermedad inmunomediada del oído interno Resumen Introducción y objetivos: La enfermedad inmunomediada del oído interno (EIOI) es una de las escasas afecciones del oído interno que pueden revertirse con tratamiento médico. Este se basa en los corticoides, si bien el tratamiento prolongado con los mismos se asocia a serios efectos adversos, lo que ha propiciado el uso de otros fármacos o vías de administración como la intratimpánica. En este estudio se analiza el papel de las terapias biológicas en el tratamiento de la EIOI. Material y métodos: Se ha realizado una búsqueda sistemática en PUBMED de aquellos estudios que examinan la respuesta al tratamiento con distintos agentes biológicos en pacientes con EIOI. Se ha analizado los criterios de inclusión y exclusión de cada estudio, así como las características de la población estudiada, el tratamiento utilizado y, los criterios de respuesta y tasa de respuesta alcanzada. Resultados: Se identificaron 13 estudios relevantes. En 8 estudios de utilizó un inhibidor del TNF␣ (etanercept, infliximab, adalimumab), en 3 un antagonista de la IL-1 (anakinra) y en el resto se empleó el rituximab, un antagonista del receptor CD20 de los linfocitos B. En la mayoría de los estudios se logró una mejoría o estabilización de la audición en más del 70% de los pacientes tratados. Conclusiones: Las terapias biológicas pueden tener un papel en el tratamiento de los pacientes con EIOI, al menos en aquellos que responden mal a los corticoides o no se consigue su estabilización. Sin embargo, son necesarios más estudios controlados y aleatorizados para conocer su eficacia. © 2012 Elsevier España, S.L. Todos los derechos reservados. Introduction Current knowledge of immune-mediated inner ear disease (IMIED)1 assumes the possibility of interfering in its evolution by stopping its progression and even improving the function of the affected organ through the use of antiinflammatory or immunomodulatory drugs, such as steroids, which are the gold standard for such treatment.2 However, IMIED remains a diagnostic challenge, since there are no fully specific markers. Nonetheless, there are therapeutic risk profiles3,4 because a significant percentage of patients do not respond adequately to treatment. These circumstances are closely related since the lack of a well-defined diagnosis may lead to the treatment of patients exhibiting no IMIED and, therefore, a lack of response to corticosteroids, as is the case with autoinflammatory diseases. Furthermore, the use of high doses of corticosteroids for long periods of time is associated with unacceptable adverse effects.5 Other treatments have also been used. However, despite being promising initially, they have not demonstrated efficacy in rigorous studies, as in the case of methotrexate,6 or have shown an inadequate adverse effect profile, as in the case of cyclophosphamide or leflunomide. All these factors have redirected research towards the search for new drugs or safer routes of administration, such as the intratympanic approach.7,8 The present study analyses the role of biological therapies in the treatment of IMIED. Biological agents are fusion proteins or monoclonal antibodies created to block specific components of the inflammatory cascade. Despite an increasing experience with the use of these drugs for other autoimmune diseases, such as rheumatoid arthritis, there is not much experience in the treatment of IMIED.9 Specifically, we have studied the role of some tumour necrosis factor (TNF) inhibitors, such as etanercept, infliximab or adalimumab, antagonists of the interleukin-1 (IL-1) receptor, such as anakinra, and other treatments such as rituximab. We highlight the use of TNF inhibitors, which act by blocking TNF, a proinflammatory cytokine especially produced by macrophages which is expressed in the inner ear during the early stages of the inflammatory response.10 We have reviewed the literature seeking publications which presented the results of the clinical use of these therapies in the treatment of IMIED. Moreover, we have also studied the effectiveness of these treatments in addressing sensorineural hearing loss occurring in the context of autoinflammatory diseases, such as Muckle---Wells syndrome or CINCA (chronic, infantile, neurological, cutaneous, and articular) syndrome. They present clinical symptoms similar to those of some systemic autoimmune diseases; however, they do not respond to corticosteroids and probably have a genetic origin.11 Material and Methods We conducted a systematic search of PUBMED for studies examining the response to treatment with different biological therapies in patients with IMIED. Secondarily, we included those studies which analysed the response to biological therapies in patients with sensorineural hearing loss secondary to other autoimmune or autoinflammatory diseases. Specifically, we used the following search strategy: (‘‘Hearing loss, Sensorineural’’ [Mesh]) AND (‘‘TNFR-Fc fusion protein’’ [supplementary concept]) OR (‘‘Hearing loss, Sensorineural’’ [Mesh] AND ‘‘Interleukin 1 Receptor Document downloaded from http://www.elsevier.es, day 06/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Review of the Biologic Agents Used for Immune-Mediated Inner ear Disease as rheumatoid arthritis and systemic lupus erythematosus (SLE).13,14 All 3 studies used similar criteria to measure the response to treatment: improvement of 15 dB in 1 frequency or 10 dB in 2 frequencies, or improvement of 12% or 15% in the recognition of words. However, in their randomised, placebo-controlled study, Cohen et al. only considered a response to treatment when these goals were achieved in the eighth week of treatment. Regarding the characteristics of the study population, these were very similar in the 3 studies, with a mean age around 50 years and a homogeneous gender distribution. It is worth noting the low prevalence of side effects in the 3 studies, which were mainly local reactions at the point of injection. The remaining studies consisted of 1 retrospective study,15 1 non-randomised, prospective pilot study16 and 1 case report presentation.17---19 The study by Van Wijk et al. evaluated the response to transtympanic administration of infliximab and was the only one out of all the studies reviewed which used this administration route. Response rates can be seen in Table 1. In the study by Matteson et al. (prospective study), hearing improved in 30% of patients and became stabilised in 57%.13 Antagonist’’ OR (‘‘Antirheumatic agents’’ [pharmacological action] AND (‘‘Hearing loss, Sensorineural’’ [Mesh]. Likewise, we reviewed the references of all selected studies seeking other potentially relevant studies. We analysed the inclusion criteria, characteristics of the study population, treatment used, treatment response criteria in each study and the response rate obtained. Finally, we highlighted whether the studies represented case series or randomised and controlled clinical trials. Results We identified a total of 13 relevant articles. Three studies analysed the response to etanercept, 2 to rituximab, 3 to infliximab, 3 to anakinra, 1 to adalimumab and, lastly, 1 study analysed the response to the combined treatment of etanercept and methotrexate. For the sake of greater clarity, studies were grouped into 3 different treatment groups. TNF-␣ Inhibitors (Etanercept, Adalimumab, and Infliximab) These agents act by binding to soluble TNF or receptorbound TNF (infliximab) or else by directly binding to the receptor (adalimumab) or competing with it (etanercept). Their use is indicated for moderate to severe rheumatoid arthritis, alone or in combination with methotrexate. They are also used in psoriasis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis. The study by Rahman et al. from 2001 was the oldest identified in this search.12 This retrospective pilot study examined the response to etanercept in a group of 12 patients with sensorineural hearing loss, of which only 1 presented findings suggestive of systemic autoimmune disease. The inclusion criteria were: (1) bilateral sensorineural hearing loss or symptoms of Meniere’s disease with recent progressive hearing loss; (2) clear response to high doses of steroids, and/or (3) presence of anti-HSP70 antibodies. Matteson et al. and Cohen et al. used similar inclusion criteria, albeit without ruling out patients with unilateral hearing loss or taking into account the results of otoblot® (antibodies against the 68 kDa protein), and excluding patients with systemic inflammatory diseases, such Table 1 225 Antagonists of IL-1 (Anakinra) Anakinra is an antagonist of the IL-1 receptor. It is indicated for moderate to severe rheumatoid arthritis in patients older than 18 years with a poor response to one or more disease modifying anti-rheumatic drugs (DMARDs), as monotherapy or in combination with other drugs, except for TNF inhibitors. The works of Rigante, Rynne, and Gerard studied the response to anakinra in patients with auto-inflammatory disease (CINCA, Muckle---Wells syndrome) (Table 2).20---22 All 3 studies consisted of clinical case report presentations. The study by Rigante et al. achieved hearing stabilisation of a 7-year-old boy who had not responded adequately to any treatment until then. The studies by Rynne and Gerard referred to patients with Muckle---Wells syndrome. The first one described a 59-yearold female who obtained an improvement of 15---30 dB in the Response to Anti-TNF␣ (Etanercept, Infliximab, and Adalimumab). First author Year Treatment Patients, n Rahman et al.12 Matteson et al.13 Cohen et al.14 Street et al.17 2001 2005 2005 2006 Morovic Vergles et al.18 Liu et al.15 Van Wijk et al.16 Staecker and Lefebvre19 2010 2011 2006 2002 Etanercept 12 Etanercept 23 Etanercept 20 Etanercept/ 1 methotrexate Adalimumab 1 Infliximab 8 Infliximab 9 Infliximab 1 iv, intravenous; NP, not provided; sc, subcutaneous; w, week. Mean age, years Stabilisation or improvement, % Dosage and administration route 47 48 52 56 91 87 12.5 100 25 mg × 2 every 7 days sc Same Same 25 mg × 2/w sc 30 57 51 35 100 0 77 100 40 mg/w 12 w 320---600 mg iv/4---12 w 0.3 ml/w 4 w transtympanic NP Document downloaded from http://www.elsevier.es, day 06/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. 226 Table 2 D. Lobo et al. Response to Anakinra in Patients With Autoinflammatory Disease. Year Number of patients Age Percentage of improvement, % Percentage of stabilisation, % Autoinflammatory disease Dosage Rigante et al.20 Rynne et al.21 Gerard et al.22 2006 1 7 years 2006 1 59 years 100 2007 1 64 years 0 Muckle---Wells syndrome Information not provided Muckle---Wells syndrome 100 mg/day 100 CINCA 1 mg/kg/day CINCA, chronic, infantile, neurological, cutaneous, and articular syndrome. frequency range of 250---4000 Hz within the first 18 weeks of treatment with anakinra. In the second study, a 64-year-old male with severe sensorineural hearing loss did not achieve any hearing improvement. Antagonists of the CD20 Receptor of B Lymphocytes (Rituximab) Rituximab is a monoclonal antibody that acts by binding to the CD20 receptor of B cells, inducing cell death via apoptosis. Rituximab in combination with methotrexate is indicated in patients with rheumatoid arthritis who present an inadequate response or intolerance to other DMARDs, including TNF inhibitors. It is also used in the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukaemia. The study by Cohen et al. was a clinical trial assessing the response to rituximab in a group of patients with progressive, idiopathic, bilateral, sensorineural hearing loss, who had previously responded to treatment with corticosteroids. A positive response was considered once this was maintained at 24 weeks of starting treatment with rituximab. The study by Orsoni et al. presented a 25-year-old female with Cogan syndrome and progressive, sensorineural hearing loss despite undergoing treatment with cyclophosphamide, methotrexate, cyclosporine, prednisone, and adalimumab. Only rituximab obtained an improvement of 16 dB at central frequencies. This gain was maintained after 12 months. Lastly, Table 3 shows the results obtained in the studies of Cohen et al. and Orsoni et al.23,24 Discussion IMIED is one of the few causes of sensorineural hearing loss that can be arrested or even reversed through appropriate Table 3 Rates of Response to Rituximab. Year Number of patients Mean age Percentage of improvement SAD Dose Cohen et al.23 Orsoni et al.24 2011 7 47 years 71% 2010 1 25 years 100% 0 1000 mg × 2 iv Cogan syndrome 500 mg iv/s 4 s iv, intravenous; SAD, systemic autoimmune disease. treatment. Patients often respond to high doses of corticosteroids; however, hearing loss often recurs when the treatment is reduced or discontinued. Treatment with high doses of corticosteroids for long periods of time is associated with unacceptable side effects, so other treatments have been tested. Thus, methotrexate has demonstrated efficacy in randomised, controlled clinical trials, whilst other immunosuppressive treatments have shown excessive toxicity, so they are not widely used at present.5,6,25,26 In this context, various biological therapies are being tested, and many are already being used for other autoimmune diseases, with a high efficacy and scarce adverse effects.9,27,28 Biological agents are fusion proteins or monoclonal antibodies specifically created to block components of the inflammatory cascade. TNF inhibitors have been the most widely used biological therapies. TNF is a proinflammatory cytokine produced by many cells, especially macrophages, which promotes inflammation by activating macrophages, stimulating the maturation and migration of dendritic cells, activating neutrophils and NK cells, increasing vascular permeability, etc. It was first isolated by Carswell et al. in 1975,29 in an attempt to identify the factors responsible for the necrosis of Meth A sarcoma. Its expression has been observed in various structures of the inner ear at an early stage of the inflammatory response.30 It is secreted by macrophages, monocytes, B and T lymphocytes, and by spiral ligament fibroblasts. It stimulates the expression of inducible nitric oxide synthase (iNOS/NOS II) in guinea pig cochlea with possible neurotoxic effects in the inner ear.31 TNF␣ is a key component of the defence against M. tuberculosis and other granulomatous diseases. Thus, screening with a chest radiography or Mantoux test is advisable before starting treatment. Although it is very rare, TNF inhibitors can induce SLE. Etanercept, a TNF␣ inhibitor, has proved effective in experimental models of autoimmune labyrinthitis in guinea pigs, with an effectiveness comparable to that of corticosteroids.32,33 Other TNF inhibitors and biological agents have been developed since then. Table 4 shows these agents, together with their mechanism of action. Fig. 1 shows the inflammatory cascade which leads to inner ear injury, showing where the various biological agents studied intervene. The percentages of improvement and stabilisation of hearing achieved in many studies appear to support the role of TNF inhibitors in stabilising hearing when corticosteroid treatment fails or is inadequate. The improvement obtained Document downloaded from http://www.elsevier.es, day 06/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Review of the Biologic Agents Used for Immune-Mediated Inner ear Disease 227 Table 4 Main Biological Agents Used in IMIED. Molecule Commercial name Synthesis Anti- Mechanism of action Cost, Dd Infliximaba Etanerceptb Adalimumabc Anakinra Rituximab Remicade® Enbrel® Humira® Kineret® Mabthera® Chimeric Humanised Humanised Humanised Chimeric TNF␣ TNF␣ TNF␣ IL-1 CD 20 Binds to soluble and bound TNF Competes with TNF receptors Binds to TNF receptor Antagonist of the IL-1 receptor Binds to CD20 receptor of B lymphocytes 2463.52 1090 4510.28 1944.24 2899.15 a b c d Chimeric human---mouse recombinant antibody, which binds to soluble and receptor-bound TNF. Dimer composed of the extracellular portion of 2 TNF␣ receptors and the Fc portion of human IgG1. Recombinant monoclonal antibody, formed by various human peptidic sequences. Cost estimated for 8 weeks of treatment at the usual dosage. in other accompanying symptoms, such as vertigo, which depends more on stabilisation of the vestibular function, is noteworthy. The randomised and controlled study by Cohen et al.14 presented worse results and led to many questions. Matteson et al.13 maintained the treatment for 24 weeks, whilst Rahman et al.12 did so for 6---12 months. However, in the study by Cohen et al.,14 etanercept was only used for 8 weeks and the response was only analysed for statistical significance at the end of the eighth week of treatment. This was based on the fact that patients with rheumatoid arthritis obtain an established response after 8---12 weeks of treatment. However, the possibility of a higher rate of response in case of more prolonged treatment is accepted. Van Wijk et al.16 suggested that the lack of response from patients in the study by Cohen et al.14 was due to the fact that they suffered quiescent disease, whilst in their study all patients had shown a recent response to corticosteroids. Furthermore, this study opened the door to intratympanic treatment with biological agents, such as infliximab. Autoantigens 2 B lymphocyte T cells (CD4RA, CD4RO) Autoantibodies Lymphokines IL12 NK, ADCC cells Immunocomplexes TNF Monokines 3 IL4 IL1 Th1 lymphocytes IL2 Monocyte macrophages IF γ IL13 Th2 lymphocytes IL4 IL10 IL13 The study of Liu et al.15 did not observe any response; however all patients were refractory to treatment with corticosteroids, methotrexate or cyclophosphamide before starting the trial with infliximab. Rituximab is a chimeric, monoclonal antibody which binds to the CD20 receptor of B lymphocytes, thus decreasing their number (Fig. 1). The scarce studies which tested rituximab offered some very promising results, with a high response rate. However, further studies are required to obtain reliable conclusions. Anakinra is an antagonist of the IL1 receptor. CINCA (chronic, infantile, neurological, cutaneous, and articular) syndrome and Muckle---Wells syndrome (urticaria, progressive sensorineural hearing loss and systemic AA amyloidosis) are part of a group of autoinflammatory fever syndromes caused by mutations in the CIAS/NALP3 gene of the 1q44 chromosome.34 These mutations seem to interrupt the mechanisms of apoptosis and lead to overexpression of IL-1, with devastating proinflammatory effects. The diagnosis is purely clinical, although nowadays it is possible to obtain a genetic diagnosis. Anakinra represents a promising new treatment for these patients, controlling and reversing the symptoms, although its possible role in the treatment of sensorineural hearing loss still needs to be elucidated. Given the small number of patients and the contradictory results, it is not possible to draw conclusions from the articles analysed. In the study by Gerard et al.,22 the patient presented a profound and established sensorineural hearing loss, which could explain the lack of response to treatment. Although these results should be analysed with caution, they may be relevant to the implementation of prospective studies. 1 Inner ear lesion Figure 1 Autoimmune mechanism suggested for IMIED. Numbers within a circle indicate the points of action of the biological agents studied: 1: etanercept, infliximab, and adalimumab act by blocking the action of TNF; 2: rituximab causes the depletion B lymphocytes by binding to their CD20 receptor; 3: anakinra is an antagonist of IL 1. ADCC: antibody dependent cellular cytotoxicity; NK: natural killer cell; TNF: tumoural necrosis factor. Conclusion Biological therapies may have a role in the treatment of patients with IMIED, at least in those who, having presented a favourable response to corticosteroids, cannot continue to use them because of their adverse effects or because they do not achieve stabilisation. However, there are still many unanswered questions. On the one hand, we must still delve deeper into the understanding of the pathophysiology and also improve Document downloaded from http://www.elsevier.es, day 06/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. 228 diagnosis; on the other hand, the fluctuating nature of the disease itself forces us to design more rigorous, randomised and controlled studies in order to differentiate between the response to treatment and the natural history of the disease. Undoubtedly, all these advances will lead to the development of new and more effective therapies, as well as a better approach and control of these patients. Conflict of Interests The authors have no conflict of interests to declare. References 1. McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol. 1979;88:585---9. 2. García-Berrocal JR, Ramírez-Camacho R, Trinidad A, Lobo D. Glucocorticoids: the best therapy for immunemediated inner ear disease. Curr Topics Steroid Res. 2004;4: 99---104. 3. Lobo D, López FG, García-Berrocal JR, Ramírez-Camacho R. Diagnostic tests for immunomediated hearing loss: a systematic review. J Laryngol Otol. 2008;122:564---73. 4. García-Berrocal JR, Ramírez-Camacho R, Trinidad A. Autoimmune hearing loss: improving diagnostic performance. Acta Otorrinolaringol Esp. 2007;58:138---42. 5. García-Berrocal JR, Ramírez-Camacho R, Lobo D, Trinidad A, Verdaguer JM. Adverse effects of glucocorticoid therapy for inner ear disorders. 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Broughton SS, Meyerhoff WE, Cohen SB. Immune-mediated inner ear disease: 10-year experience. Semin Artritis Rheum. 2004;34:544---8. 27. Moreland LW, Cohen SB, Baumgartner SW, Tindall EA, Bulpitt K, Martin R, et al. Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. J Rheumatol. 2001;28:1238---44. 28. Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum. 2007;56: 3896---908. 29. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975;72: 3666---70. 30. Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM. Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation. J Assoc Res Otolaryngol. 2003;4:139---47. 31. Hess A, Bloch W, Huverstuhl J, Su J, Stennert E, Addicks K, et al. Expression of inducible nitric oxide synthase (iNOS/NOS II) in the cochlea of guinea pigs after intratympanical endotoxintreatment. Brain Res. 1999;830:113---22. 32. Wang X, Truong T, Billings PB, Harris JP, Keithley EM. Blockage of immune-mediated inner ear damage by etanercept. Otol Neurotol. 2003;24:52---7. Document downloaded from http://www.elsevier.es, day 06/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Review of the Biologic Agents Used for Immune-Mediated Inner ear Disease 33. Lobo D, Trinidad A, García-Berrocal JR, Verdaguer JM, RamírezCamacho R. TNFalpha blockers do not improve the hearing recovery obtained with glucocorticoid therapy in an autoimmune experimental labyrinthitis. Eur Arch Otorhinolaryngol. 2006;263:622---6. 229 34. Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002;46:2445---52.