Autoimmune inner ear disease (AIED) is a rare form of sensorineural hearing loss that involves periods of fluctuating loss triggered by unknown stimuli. Compared with sudden sensorineural hearing loss, this condition's hearing loss onset is believed be slower, evolving between three and 90 days (JAMA. 2003;290:1875 http://bit.ly/2tYBTWM). Both ears are typically affected, although both ears may not fluctuate simultaneously. Only 30 percent of these patients are also afflicted with a systemic autoimmune disease (Laryngoscope. 1988;98:251 http://bit.ly/2tYDgVv), and whereas there is usually a strong family history for autoimmune disease, AIED is not typically observed in multiple family members. About half of the patients experience vertigo during the course of the disease, though hearing loss may occur in the absence of concomitant vertigo. The use of serology to firmly establish patient diagnosis has been problematic as the presence of autoantibodies is infrequent, diverse, and usually low in titers (Curr Opin Neurol. 2006;19:26 http://bit.ly/2tYEtMc).
The mainstay of treatment for AIED remains to be corticosteroids. Although 60-70 percent of patients initially respond to corticosteroids, most of these patients become less responsive over time (Semin Arthritis Rheum. 2004;34:544 http://bit.ly/2tYwGOL). Therapeutic options beyond corticosteroids is limited. Methotrexate, for example, was comparable to placebo in maintaining any hearing improvement following corticosteroid treatment (JAMA. 2003 http://bit.ly/2tYBTWM). Similarly, systemic tumor necrosis factor (TNF) antagonism was comparable to placebo, although direct delivery to the cochlea appeared to be more beneficial for hearing recovery in two smaller studies (Otol Neurotol. 2005;26:903 http://bit.ly/2tYFofI; Audiol Neurootol. 2006;11:357 http://bit.ly/2tYVSEG; Otol Neurotol. 2014;35:1515 http://bit.ly/2tZ1b6T). In a small, open-label, early-stage clinical trial for corticosteroid-resistant AIED, systemic IL-1 inhibition appeared to correlate with hearing improvement, and the results exceeded the standard reference therapy of oral corticosteroids (J Clin Invest. 2014;124:4115 http://bit.ly/2tYDcVF; Otol Neurotol. 2005;26:908 http://bit.ly/2tYZ1Es). Although promising, these results must be validated in a larger placebo-controlled trial.
Recently, a new class of systemic autoinflammatory diseases that causes sensorineural hearing loss has been described. Called cryopyrin, it is associated with periodic syndromes or CAPS, distinguished by its IL-1 dysregulation molecular signature. Within the CAPS family, the Muckle-Wells syndrome, a rare autosominal dominant disease, is most similar to AIED. A gain-in-function mutation of the gene NLRP3 releases excessive IL-1, thereby causing sensorineural hearing loss, uveitis, and transient skin rashes, among others (Nat Genet. 2001;29:301 http://bit.ly/2tZ92Si; Arthritis Rheum. 2004;50:607 http://bit.ly/2tYKYii). Muckle-Wells closely resembles Cogan's syndrome, an autoimmune disease that affects both the auditory and ocular systems (Arch Ophthal. 1945;34:248 http://bit.ly/2tYumY3).
The inflammation that results in clinical autoimmune and autoinflammatory hearing loss is likely initiated by the innate immune response of cochlear macrophages and microglia that produce the pro-inflammatory cytokines TNF and IL-1. Whereas TNF appears to be related to steroid-sensitive AIED, IL-1 appears to predominate in steroid-resistant AIED (Arch Otolaryngol Head Neck Surg. 2012;138:1052 http://bit.ly/2tYUDW5; J Immunol. 2011;186:1870 http://bit.ly/2tYHigB). Specific targeted immunotherapy against these cytokines and downstream signaling proteins have been met with mixed results, highlighting the need to identify which cytokines and inflammatory proteins are pathologically active in AIED. Further characterization of the biologic mechanisms that control disease onset or progression is needed to identify novel therapies.