Rheumatology 2013;52:780–789

RHEUMATOLOGY doi:10.1093/rheumatology/ket009
Advance Access publication 21 February 2013

Review
Autoimmune sensorineural hearing loss: the
otology–rheumatology interface

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Tamara Mijovic1, Anthony Zeitouni1 and Inés Colmegna2

Abstract
Autoimmune sensorineural hearing loss (SNHL) is a rare clinical entity characterized by a progressive
fluctuating bilateral asymmetric SNHL that develops over several weeks to months. Vestibular symptoms,
tinnitus and aural fullness are present in up to 50% of patients. Due to the lack of specific diagnostic tests,
both clinical suspicion and responsiveness to corticosteroids are the pillars for the diagnosis of autoim-
mune SNHL. The evaluation of patients in whom this condition is suspected should include a detailed
history and physical examination, an audiogram, an MRI and a limited laboratory workup to exclude
R EV I E W

secondary causes of hearing loss. The low frequency of this condition, the heterogeneity in the designs
of the available studies and the absence of randomized trials comparing treatment responses and
assessing long-term outcomes are some of the factors accounting for the limited evidence to guide the
clinician in the approach to the diagnosis and treatment of autoimmune SNHL.
Key words: hearing, deafness, autoimmune inner ear disease (AIED), sensorineural hearing loss (SNHL),
autoimmune cochleopathy, immune-mediated cochleovestibular disease, fluctuating hearing loss.

Introduction AIED accounts for fewer than 1% of all cases of hearing

Sensorineural hearing loss (SNHL) results from dysfunc-
tion of the inner ear, the vestibulocochlear nerve or the
central processing centres of the brain. In contrast, con-
ductive hearing loss results from a defect in sound trans-
mission through the external ear, tympanic membrane or
middle ear.
In 1958, Lehnhardt first described an ‘antigen–antibody
reaction’ in 13 patients with progressive bilateral SNHL. In
his report, nine patients developed subsequent involve-
ment of the contralateral ear, suggesting the possibility
that an injury on one side sensitized the body to a coch-
lear antigen leading to hearing loss in the opposite ear [1].
In 1979, McCabe [2] describes one patient from a series of
18 with idiopathic bilateral progressive SNHL responsive
to steroids, proposing the term autoimmune SNHL. This
condition is also known as autoimmune inner ear disease
(AIED), autoimmune cochleopathy or immune-mediated
cochleovestibular disease [3, 4].
1
Department of Otolaryngology, Head and Neck Surgery and 2Section
of Rheumatology, Department of Medicine, McGill University,
Montreal, Quebec, Canada.
Submitted 19 October 2012; revised version accepted
17 January 2013.
Correspondence to: Inés Colmegna, Section of Rheumatology,
Department of Medicine, Royal Victoria Hospital, M11-32, 687 Pine
Avenue, Montreal, Quebec H3A 1A1, Canada.
E-mail: ines.colmegna@mcgill.ca
loss; however, this could be an underestimation based
on the absence of specific diagnostic tests [3]. AIED is
one of the few forms of sensorineural deafness that can
potentially be treated.
Herein, we summarize the evidence on the pathophysi-
ology and current approach to the diagnosis and treat-
ment of adults with bilateral, progressive, fluctuating
hearing loss. These data derive from a systematic
review of the literature conducted in MEDLINE (1996 to
October 2012) and EMBASE (1996 to October 2012).
The search strategy included the terms autoimmune
and hearing loss both as medical subject heading and
keywords.
Definitions
In the absence of a reliable marker for AIED, the disease
is defined by an appropriate clinical presentation, by ex-
clusion of other known causes of SNHL and by a positive
response to steroid therapy.
McCabe’s original description states that the time
course of the hearing loss is the best clue to AIED diag-
nosis: ‘a period of progression of the deafness over weeks
or months, not hours nor days nor years’ [2]. This course
distinguishes AIED from sudden deafness and from
age-related hearing loss (i.e. presbycusis). AIED is defined
as primary when the pathology is restricted to the ear. In
up to a third of cases, AIED occurs in the context of a

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TABLE 1 Systemic autoimmune diseases associated with
AIED
Disease
Vogt–Koyanagi–Harada syndrome
Cogan’s syndrome
Susac’s syndrome
SLE
Antiphospholipid syndrome
RA
Systemic vasculitis
Panarteritis nodosa
Granulomatosis with polyangiitis
SSc
Goodpasture syndrome
Behçet’s disease
Sarcoidosis
SS
Hashimoto thyroiditis
Relapsing polychondritis
Myasthenia gravis
Polymyositis–dermatomyositis
Crohn’s disease
Ulcerative colitis
AS
Guillain–Barré syndrome
Multiple sclerosis
Adapted from Acta Otolaryngol 2006;126:1012–21.
systemic autoimmune disease and is defined as second-
ary [5]. Table 1 provides a list of the systemic autoimmune
diseases associated with AIED; the true frequency and the
risk factors for developing AIED in the context of systemic
autoimmune diseases are unknown.
Although there are no uniformly accepted criteria to
diagnose AIED, the presence of bilateral SNHL of 30 dB
or more at any frequency with evidence of progression in
at least one ear on two serial audiograms performed less
than 3 months apart is often used for case definition [6, 7].
Pathophysiology
The pathogenesis of bilateral, progressive, fluctuating
hearing loss is unknown and therefore this represents
one of the most controversial and challenging diseases
in otology [8]. Since diagnostic biopsy of the human
inner ear is not feasible, animal models are of major rele-
vance in studying the aetiopathogenesis of this disease.
Viral infections or vascular disorders leading to cochlear
or cochlear nerve damage have been postulated as
mechanisms in bilateral, progressive, fluctuating hearing
loss. However, up to date, there is very limited evidence
to support the pathogenetic role of viral or vascular
injuries [8].
The strongest pathogenic evidence is that of an
immune-mediated disease. The inner ear is not an im-
munologically privileged site and may mount an immune
response against foreign and self-antigens damaging
sensory structures within it [9–11]. Both humoral and
www.rheumatology.oxfordjournals.org
Autoimmune inner ear disease
cell-mediated mechanisms are involved in the autoim-
mune injury to the inner ear. Cochlear innate immunity
has been proposed to contribute to the initiation of a
local adaptive immune response following antigen chal-
lenge. Briefly, as a consequence of a yet undefined trigger
(i.e. antibody cross-reactivity, viral injury, trauma, vascular
insult, surgical damage and others) damaging the inner
ear, lymphocytes from the systemic circulation are
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exposed to proteins of the cochlea. Animals immunized
with inner ear homogenate (reviewed in [12]) develop an
immune reaction in the endolymphatic sac, which is a
critical organ in processing and modulating immunity in
the inner ear [13, 14]. Immune cells from the systemic
circulation penetrate the blood–labyrinthine barrier to
reach the endolymphatic sac [3]. Specifically, the blood
vessels of the spiral modiolar vein adjacent to the scala
tympani seem to be the initial site for lymphocyte entry to
the inner ear [15]. Chronic activation of helper T lympho-
cytes reactive against self-proteins leads to the destruc-
tion of sensory and supporting cells within the cochlea.
IL-1a, IL-2, TNF-a and NF-kB, cytokines essential in the
initiation, modulation and amplification of the immune
response, are expressed by infiltrating cells in the endo-
lymphatic sac [16, 17]. The pathogenic role of autoreac-
tive T-cell lines has been demonstrated by their passive
transfer to naı̈ve animals resulting in an inner ear autoim-
mune response [18, 19]. Thus, a critical task is to identify
the inner ear antigens that trigger this autoreactive re-
sponse. A proposed candidate is recombinant mouse
cochlin, an extracellular matrix protein highly and specif-
ically expressed in the inner ear [20]. When challenged
with cochlin antigen, mice have robust T-cell proliferative
responses, increased production of IFN-g and cochlear
inflammation [21]. Moreover, this form of primary AIED
could be passively transferred into naı̈ve recipient mice
by CD4+ T cells. Of relevance, elevated levels of cochlin
antibodies and increased frequencies of cochlin-specific
IFN-g-producing T cells have been found in patients with
AIED [22, 23]. These studies provide evidence implicating
an adaptive immune response, against an inner-ear-spe-
cific target antigen, with AIED. They also provide experi-
mental confirmation that AIED may be a T-cell-mediated
organ-specific autoimmune disorder of the inner ear [21].
Further data supporting the role of T cells in AIED derives
from a murine study treated with adipose-derived mesen-
chymal stromal cells. This cell-based therapeutic strategy
significantly improved hearing function via the down regu-
lation of T-cell responses and the suppression of Th1/
Th17-type cytokines through the generation of IL-10-
secreting T-reg cells [24].
Circulating antibodies against a number of inner ear anti-
gens leading to cytotoxic antibody-mediated damage
(type II response) or immune complex-mediated damage
(type III response) have been implicated in the pathogen-
esis of hearing loss in animal models. Sera from 70% of
patients with bilateral SSHL of unknown aetiology contain
antibodies capable of immunostaining human inner ear
tissues. Autoantibodies against type II collagen, type IX
collagen, Raf-1 protein, the major peripheral myelin
protein P0, B-actin, cochlin, choline transporter-like
781
Tamara Mijovic et al.
protein 2 (CTL2), cell-density enhanced protein tyrosine
phosphatase-1 and connexin 26 have all been described
in AIED [4, 25, 26]. The stria vascularis, fibrocytes of the
spiral ligament and supporting cells are the anatomical
targets of those autoantibodies.
Harris and Sharp [27] were the first to show that western
blots of serum from patients with AIED had an antibody
directed against the 68-kDa inner ear antigen latter char-
acterized as a heat shock protein (HSP70) found in the
inner ear. Of relevance, elevated HSP70 antibodies are
not the underlying cause of hearing loss but rather a non-
pathogenetic epiphenomenon [28, 29]. However, antibo-
dies to HSP70 are found in AIED patients and their
presence was correlated with responsiveness to steroid
treatment [6]. The sensitivity and specificity of anti-HSP70
for the diagnosis of AIED was 42% and 90%, respectively,
and their positive predictive value 91% [30].
In experimental models of AIED (i.e. the immunization of
a guinea pig with swine inner ear antigens in complete
Freund’s adjuvant), it is possible to induce cochlear dys-
function, endolymphatic hydrops and development of
antibodies to 68-, 50-, 45- and 27-kDa molecular weight
inner antigens. The target antigen seems to be a choline
transporter-like protein 2 (CTL2), a member of the cho-
line transporter-like protein family linked to acetylcholine
synthesis, which is an inner ear glycoprotein of 68 and
72 kDa [31].
In summary, both arms of the immune system, innate
and adaptive, are implicated in the processes ultimately
leading to the histopathological features in the cochlea of
patients with AIED. Those include damage to the organ of
Corti, retrograde neural degeneration to the level of the
spiral ganglion, endolymphatic hydrops, stria vascularis
dystrophy, neo-fibroosteogenesis in the basal turn of the
cochlea, fibrosis of the endolymphatic sac and lympho-
cytes in the labyrinthine membrane compartment [32–35].
Clinical manifestations
AIED most commonly affects people in the third to sixth
decades of life and presents with unilateral or bilateral
SNHL that progresses over several weeks to months
[2, 36]. This time course of the hearing loss is the best
clue to the diagnosis. Although at presentation 50% of
patients report unilateral hearing loss, audiological evalu-
ation demonstrates asymmetrical but bilateral involvement
in the vast majority of cases (80–100%) [2]. Fluctuations in
hearing are common but the overall course is one of pro-
gressive deterioration of auditory function [37–39].
Vestibular symptoms such as generalized imbalance,
motion intolerance, ataxia and positional or episodic low-
grade vertigo are present in 50–80% of patients [3, 35, 37];
25–50% have tinnitus and aural fullness meeting criteria for
Menière’s disease [37]. In fact, during the first months, the
differential diagnosis between Menière’s disease and AIED
can be difficult. The more aggressive course of AIED will
allow the differentiation. Moreover, some forms of bilateral
Menière’s disease seem to have an underlying autoimmune
pathology [40]. Some authors suggest that any patient
diagnosed with unilateral Menière’s disease who develops
782
symptoms in the contralateral ear should undergo workup
for an autoimmune aetiology [37]. As stated earlier, up to a
third of AIED cases occur in the context of a systemic auto-
immune disease, and unusually can be the first manifest-
ation of the latter.
Diagnosis
Essentially all patients with AIED initially present to and are
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evaluated by otolaryngologists who often consult rheuma-
tologists to rule out an underlying systemic autoimmune
disease or to assist in monitoring the immunosuppressive
therapy. Fig. 1 proposes a step-by-step diagnostic ap-
proach. The following features should be determined
from the history in any patient presenting with hearing
loss: (i) length of time over which the hearing loss has de-
veloped, (ii) associated otological symptoms (tinnitus, ver-
tigo, pain, discharge and pressure) and (iii) predisposing
factors (i.e. noise exposure, chemotherapy or antibiotic
treatments, previous ear surgery, trauma, meningitis or
family history of hearing loss). Differentiating between
AIED and sudden hearing loss is critical. Although at the
initial presentation AIED may be more evident in one ear, it
progresses over weeks to months, involving both ears. In
contrast, sudden hearing loss is unilateral and develops in
72 h or less. In addition to the specific otological history, it is
relevant to perform a complete review of systems since in
15–30% of cases patients with AIED have or will develop a
systemic autoimmune disease (Table 1) [36]. Thus, the
presence of recurrent or chronic ocular disease, nephritis,
arthritis, pneumonitis, sinusitis, photosensitivity and symp-
toms suggestive of inflammatory bowel should be estab-
lished. In addition to causing SNHL, autoimmune diseases
can lead to conductive hearing impairment. In fact, up to a
third of patients with granulomatosis with polyangiitis have
conductive hearing loss secondary to effusions from
granulomatous involvement of the middle ear and eusta-
chian tube mucosa [41]. Similarly, eustachian tube dys-
function is not uncommon in patients with relapsing
polychondritis [42], while the ossicular chain can be af-
fected by RA, leading to conductive hearing loss in more
than 15% of RA patients [43].
Therefore, the first step in the evaluation of a patient
presenting with hypoacusia is to define whether the hear-
ing loss is sensorineural or conductive. This is based on
the physical examination, specifically on the otoscopy
findings and tuning forks tests. The magnitude of hearing
loss is then defined by an audiogram where air and bone
conduction hearing thresholds are quantified and com-
pared. Fig. 2 shows a representative example of an audio-
gram of conductive hearing loss and SNHL. The
audiological assessment is a crucial part of both the initial
diagnostic evaluation and all subsequent follow-ups of
patients with hearing loss, allowing the characterization
of the severity, frequencies involved and symmetry. The
two most important components of the audiological as-
sessment in patients with AIED are (i) pure-tone air con-
duction threshold testing, the goal of which is to obtain a
representation of the softest intensity heard across fre-
quencies (0.25, 0.5, 1, 2, 3, 4, 6 and 8 kHz) comparing
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 Autoimmune inner ear disease

FIG. 1 Algorithm for the approach to a patient with hearing loss.

Duration (weeks to months)

Associated otological symptoms (tinnitus, vertigo, pain, discharge, pressure- 50% of patients)
History Rule out known causes of SNHL (noise exposure, medications, infections, trauma, surgery, family history)
Review of symptoms for autoimmune disorders (ocular, renal, pulmonary, ENT, GI and skin involvement)

Physical

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Examination Otoscopy and tuning forks (SNHL)

Audiogram Asymmetrical SNHL

MRI Exclude retrocochlear pathology (no acoustic neuroma, multiple sclerosis, metastatic lesions or ischaemia)

Labs Rule out other causes of SNHL and associated autoimmune disorders (CBC, ESR, anti-dsDNA, anti-
SSA/B, antiphospholipid treponemal Ab absorption test)

Suspect
AIED

Consult OTL,
Response: continue steroids until
Trial of steroids Repeat audiogram stabilization and taper in 6 months
Rheumatology
& Audiology
(1 mg/kg/d x 4weeks)
No response: taper steroids over
10 days

OTL: otolaryngologist; CBC: complete blood count; anti DS-DNA: anti-double stranded DNA antibody.

observed threshold with normative data [pure-tone aver-
age (PTA) is the arithmetical average of thresholds] and (ii)
word discrimination, which probes the ability to perceive,
process and verbally reproduce phonological units that
comprise spoken words. Speech discrimination score/
word intelligibility score (WIS) is the percentage of words
a patient can repeat at a comfortable listening level. A WIS
of 70% or more is considered indicative of good potential
for spoken communication. So maintaining or reaching a
WIS of 70% is a good clinical outcome. Table 2 summar-
izes the functional impact of different degrees of hearing
impairment.
The next relevant step is to exclude other disorders that
can mimic AIED (i.e. multiple sclerosis, malignancies and
otosyphilis) [36]. Based on expert opinion, the recom-
mended routine serology tests in patients with AIED
include complete blood count, ESR, RF, ANA test, anti-
dsDNA antibodies, anti-SSA/B antibodies, antiphospholi-
pid antibodies, ANCA, C3 and C4 complement levels,
HIV and fluorescent treponemal antibody absorption test
[30, 44, 45]. In the absence of symptoms and signs of
autoimmune diseases, the value of including serology
testing appears limited [46, 47]. Moreover, positive results
of those tests are not predictive of improvement following
steroid treatment [39]. Serology studies for viral infections
are not recommended in AIED [48].
If the cause of the hearing loss is not identified, particu-
larly in patients with asymmetric SNHL, an MRI should be
ordered to rule out retrocochlear pathologies such as
acoustic neuroma, intracranial metastases, demyelinating
or ischemic diseases. AIED is suspected when no clear
aetiology is found in the imaging studies, and there is pro-
gression of the documented SNHL that is too slow to be a
sudden SNHL (which is unilateral and defined as develop-
ing over 72 h), but too fast to be presbycusis (which
develops over many years).
Despite significant efforts, to date there are no reliable
diagnostic tests for AIED. Lymphocyte migration inhibition
assays and lymphocyte transformation tests have initially
been included as part of the diagnostic approach; how-
ever, their diagnostic accuracy remains undetermined.
The use of the enzyme-linked immunospot (ELISPOT)
assay to assess the frequencies of peripheral blood
T cells capable of producing IFN-g in response to hom-
ogenates of human inner ear tissue in patients with AIED
was tested in a small study including 12 patients. This
study showed that 25% of AIED patients have increased
frequencies of inner-ear-specific IFN-g-producing T cells
in peripheral blood [23, 49]. Similarly to cellular assays,
serological tests to detect antibodies against inner ear
antigens lack sufficient specificity to be used as diagnos-
tic tools [50]. The OtoBlot assay, a commercially available
western blot assay for anti-hsp70 antibodies, has low sen-
sitivity (50%) [29, 47, 51, 52]. More recently, anti-CTL-2
antibodies were demonstrated in 50% of AIED sera; how-
ever, this test is not commercially available and its

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Tamara Mijovic et al.

FIG. 2 Typical audiograms of conductive and sensori- TABLE 2 Scales of hearing impairment and their
neural hearing loss. functional implications based on PTA and speech
discrimination score (SDS)

Functional implication in
Degree of terms of need for hearing
PTA (dB) impairment aid and lipreading

10 to 15 Normal No

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16–25 Slight Possibly
26–40 Mild Probably
41–65 Moderate Definitely
66–95 Severe Definitely
>95 Profound Definitely

Degree of Functional implication on

SDS (%) impairment conversational abilities

90–100 Normal None

75–90 Mild Slight, comparable to a
conversation over the
phone
60–75 Moderate Moderate difficulty
50–60 Severe Marked difficulty in
following a
conversation
<50 Profound Unable to follow running
speech

Adapted from Semin Arthritis Rheum 2004;34:538–43, with

permission from Elsevier.

capacity occur. A significant change in hearing is defined

by any of the following criteria: a threshold shift of 15 dB or
more in one frequency; a threshold shift of 10 dB or more
at two or more consecutive frequencies; 10 dB or more
change in PTA [37, 56–59]; 12–20% or above change in
discrimination score at 40 dB sensation level [7, 60, 61]. In
addition, to be considered as improvement in hearing,
some authors will request no additional threshold loss at
any other frequency and no additional loss in discrimin-
ation in either of the ears [52].

(A) Conductive hearing loss: there is a gap between the
hearing thresholds through air and bone. (B) Sensorineural
hearing loss: the bone and air conduction curves follow
each other.
diagnostic value needs to be confirmed in larger studies
[53]. The usefulness of PET for assessing active disease is
controversial [54, 55].
Treatment
A multidisciplinary team that includes an otolaryngologist,
a rheumatologist and an audiologist should treat a patient
with AIED, monitor therapeutic responses and prevent
side effects associated with immunosuppressants.
Patients with AIED should be followed with audiograms
on a monthly basis until their hearing stabilizes, and
every 6 months thereafter unless changes in the hearing
Steroids
Corticosteroid therapy is the mainstay of AIED treatment
due to its immunosuppressive properties and its effects on
the modulation of sodium transport. There are no prospect-
ive randomized clinical trials on which to base the dose,
route and length of the corticosteroid treatment. Moreover,
although many patients have short-term response to ster-
oids, the response is generally not sustained [62].
The most widely used regimen by otologists is an empiric
treatment protocol proposed by Rauch et al. [7] based on
150 patients in whom autoimmune inner disease was clin-
ically suspected. Initial therapy in adults is a 60 mg/day or
1 mg/kg/day therapeutic trial of prednisone for 4 weeks.
Patients’ hearing is tested at the initiation of therapy and
1 month later. A response is documented at the end of
4 weeks in 50–70% of cases [38] and those patients con-
tinue therapy until monthly audiograms demonstrate stabi-
lization [63]. At that point, steroids are tapered over 8
weeks to a maintenance dose of 10 mg for a total treatment

784 www.rheumatology.oxfordjournals.org

of at least 6 months. Relapses that are associated with
treatment duration of less than 6 months require escal-
ation of the dosage until stabilization is achieved. In pa-
tients who fail to respond to the initial 4-week trial,
steroids are tapered over 12 days.
Steroid-associated adverse effects occur in 15% of
AIED patients during the first month of treatment and 6%
have to discontinue steroid therapy [56]. Several strategies
have been proposed to overcome this problem. Some au-
thors have suggested the use of shorter steroid regimens
[38]; however, those might be associated with higher rate
of relapse [3]. The use of systemic mineralocorticoids
(aldosterone and fludrocortisone) alone or in combination
with glucocorticoids seems to be useful in animal models
but has not been tested in humans [64, 65]. Intratympanic
steroid injections have been tested in AIED patients refrac-
tory to steroids [66]. Despite high penetration of transtym-
panic methylprednisolone into the cochlear fluids [67], the
evidence supporting its use in AIED is limited. In a small
retrospective case series of 11 patients, transtympanic
6-methylprednisolone was safe and useful. Those pa-
tients received weekly injections of 6-methylprednisolone
(0.3–0.5 ml, 40 mg MP/ml) for 2 months and 54% of them
had hearing improvement with significant reduction of the
vestibular symptoms [66]. Some patients prefer to avoid
or cannot tolerate the side effects of steroid therapy and
in those cases consideration may eventually need to be
given to cochlear implants if the patient deteriorates to pro-
found hearing loss.
Non-steroidal immunosuppressants
A significant number of patients with AIED have pri-
mary or secondary response failure to steroids, are
steroid dependent or experience unacceptable side ef-
fects. In these patients, alternative immunosuppressive
approaches and steroid-sparing agents are required.
Cyclophosphamide appears to be an effective therapy
and its use in association with steroids was first described
in McCabe’s series [2]. However, the extended follow-up
of patients treated with cyclophosphamide for other
benign conditions has been associated with a high inci-
dence of serious drug-related toxicities prompting
the search for other immunosuppressive options. The
evidence supporting the use of ciclosporin A [57], MMF
[37, 58] and AZA [37, 60] in AIED is based on case reports
and small case series and not conclusive. We will discuss
agents for which stronger evidence is available.
Methotrexate
(MTX 7.5–25 mg/week) has been used as a prednisone-
sparing treatment for refractory autoimmune hearing loss
or as an adjunct to maintain or further improve the symp-
toms. Non-randomized studies including a prospective
observational study of 53 patients demonstrated good tol-
erance and an overall 70% response rate with vertigo
improving in 69%, hearing loss in 53% and tinnitus in
26% [68]. Moreover, in that study, most patients were
able to stop therapy after 1–2 years without recurrence
of symptoms [68]. In another prospective 12-month
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Autoimmune inner ear disease
open-label study including 17 patients with refractory
autoimmune hearing loss, MTX treatment was associated
with hearing improvement in 65% of the cases, stabiliza-
tion in 23% and worsening in 12% [69]. A discrepancy
between rates of improvement based on audiometric
parameters (65%) and on patient’s perception (35%)
was evidenced in this study raising the issue of using
the latter as a relevant outcome for future intervention
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studies [69].
In 2003, the only prospective, multicentre, randomized,
double-blind, placebo-controlled trial in AIED was
reported. This trial was designed to assess the efficacy
of long-term MTX (52 weeks, MTX dose: 15 mg/week) in
the maintenance of initial hearing improvement in
response to prednisone therapy in patients with primary
AIED. The study included 67 patients and was terminated
early due to no apparent benefit of MTX over placebo in
maintaining clinical response during prednisone tapering
[61]. However, this study did not assess the impact of
MTX on vestibular symptoms nor hearing fluctuations
over time, which previous MTX open-label studies re-
ported to improve [66].
Biologics
Almost every biologic agent has been used for the treat-
ment of AIED. Most of the available evidence on these
agents derives from observational studies, case reports
and case series, which can be confounded by selection
and publication bias. There are no randomized clinical
trials assessing the effectiveness of the use of specific
biologics in AIED.
Cytokine modulation
Blocking TNF-a, both systemically and locally, has shown
promising results in models of AIED [70]. In animals, the
efficacy of etanercept was similar to that of glucocortic-
oids as a primary treatment modality [71]. In humans,
TNF-a blockers have been used in refractory cases
but not as a first line of therapy. Overall, the avail-
able evidence failed to demonstrate a significant ef-
fect of anti-TNF agents on hearing outcomes in these
patients.
A retrospective case series of 12 patients with AIED
who did not respond to conventional stabilization thera-
pies but showed initial response to high-dose prednis-
one, or who experienced side effects with conventional
therapy, were treated with etanercept 25 mg s.c. twice
weekly for 6 months. Improvement or stabilization of
hearing and tinnitus was observed in 92% of the patients
[72]. In addition, seven of eight patients who had vertigo
(88%) and eight of nine patients who had aural fullness
(89%) had resolution or significant improvement of their
symptoms. In contrast to these results, an open-label
prospective pilot study of 23 patients with bilateral im-
mune-mediated cochleovestibular disorders treated with
etanercept for 24 weeks (25 mg subcutaneously twice
weekly) did not suggest substantial efficacy, with only
30% of patients showing improvement in audiometric
criteria [55]. In this study, hearing did not change in
785
Tamara Mijovic et al.
57% of patients, leaving unanswered the question of
whether etanercept might have a role in disease stabi-
lization when steroid treatment is inadequate.
Subsequently, a randomized controlled pilot trial includ-
ing 20 patients with AIED showed that treatment with
etanercept 25 mg twice weekly over 8 weeks was no
better than placebo in improving hearing [73]. The draw-
backs of this study were the small sample size, length of
treatment and the inclusion of a heterogeneous patient
population with variable disease duration with multiple
previous treatments.
A recent retrospective review of eight patients with
suspected autoimmune hearing loss refractory to all
standard treatments treated with infliximab failed to docu-
ment positive therapeutic responses based on objective
hearing measurements [74]. Since antibodies have been
demonstrated to cross the round window membrane [75,
76] and since TNF-a blockers were not found to be oto-
toxic, transtympanic infliximab administration was tested
[77]. In a prospective pilot study nine patients diagnosed
with AIED with initial response to oral steroids were trea-
ted with 0.3 ml of infliximab once weekly for 4 weeks
through a transtympanic tube and a MicroWick.
Response defined as improvement in hearing loss with
steroid tapering and a reduction in the relapse rate was
observed in seven patients [77].
A single case suggesting the benefit of adalimumab
in conjunction with MTX for the control of AIED [59] was
challenged by two reports of de novo AIED associated
with this monoclonal antibody [78].
A recent study evaluating the pathways that control
corticosteroid responsiveness in 47 patients with AIED
has shown that increased levels of IL-1b expression are
associated with corticosteroid resistance, suggesting a
role for IL-1b inhibition in clinical corticosteroid non-
responders [79].
Cell modulation
Rituximab (anti-CD20 mAb) was tested in an open-label
study of seven patients with primary immune-mediated
inner steroid-responsive AIED. A course of rituximab
(1000 mg i.v. for two doses 2 weeks apart) prior to starting
prednisone tapering was associated with sustained re-
sponse (evaluated at week 24) following steroid discon-
tinuation in five out of seven patients (24-week follow-up)
[80]. The results of this pilot study support the evaluation
of rituximab in a properly designed randomized clinical
trial [80].
In summary, the current evidence supporting the use of
steroid-sparing agents among them biologic agents as a
treatment for AIED is still anecdotal. Properly designed
randomized controlled trials are necessary to establish
the efficacy of biologics as the treatment of AIED. Given
the high cost of these agents, if efficacy is proven, cost-
effectiveness studies comparing them to the alternative of
a cochlear implant will certainly be warranted before they
become part of the standard treatment.
786
Plasmapheresis
The benefit of plasmapheresis (PMP) for AIED was evalu-
ated in studies including small number of patients (8–21 pa-
tients). Luetje et al. evaluated the long-term hearing
outcome in 16 patients who had tried other treatments
without success and received PMP on alternate days for
cycles of three exchanges. The average follow-up of these
patients was 7 years. The authors suggest that 39% of
Downloaded from https://academic.oup.com/rheumatology/article/52/5/780/1816947 by University of South Florida user on 06 October 2020
the ears met the criteria for hearing improvement or
stability and 25% of the patients required continuing
immunosuppressive drugs [81]. The precise role of PMP
in AIED and its relation to immune suppression needs to be
defined.
Cochlear implantation
The subset of patients with AIED who develop profound
irreversible bilateral SNHL who no longer benefit from
hearing aid amplification become candidates for cochlear
implantation [82]. Outcome studies have demonstrated
excellent results and performance above average in
implanted AIED patients, compared with patients with
other causes of deafness [82–84].
Conclusion
The absence of reliable markers for AIED has forced
clinicians to define the disease based on its clinical pres-
entation, exclusion of other known causes, and a positive
response to steroid therapy. In every patient who has pro-
gressive bilateral SNHL with no other explainable cause,
the diagnosis of AIED should be considered, the associ-
ation with a systemic autoimmune disease evaluated and
a trial of corticosteroids attempted.
Rheumatology key messages
. AIED is a steroid-responsive fluctuating progressive
bilateral asymmetrical SNHL that develops over
weeks to months.
. No specific diagnostic tests for AIED exist and
15–30% of cases have an associated systemic
autoimmune disease.
. Glucocorticoids remain the mainstay of AIED
treatment.
Disclosure statement: The authors have declared no
conflicts of interest.
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