Discussion
AIED is a rare cause of bilateral SNHL, accounting for <1% of
cases, with a yearly incidence of <5 per 100 000.[2] It was described by McCabe in 1979 following a
case series involving 18 patients who presented with bilateral SNHL
(>30 dB for at least 3 frequencies) that showed clinical and
audiometric improvement to immunosuppressive therapy, with no clear
cause. [1, 4] The hearing loss in AIED is
characterised by its bilateral, asymmetric and fluctuating nature.[6,7] Patients can also report tinnitus and ear
fullness (25-50%), and vestibular symptoms such as disequilibrium,
ataxia, nystagmus and episodic or positional vertigo (50%).[2, 7] It has a rapidly progressive onset,
developing between 3 to 90 days.
The pathogenesis is not completely understood and studies on AIED have
been difficult due to (1) the limited anatomical access to the cochlea,
(2) unreliable data from peripheral blood immune system and (3) a lack
of an ideal animal model. [5] The proposed
mechanism for AIED is thought to be an uncontrolled, combined humoral
and cell-mediated reaction against inner ear antigens[2, 3] which promotes autoantibody formation and
pro-inflammatory T-cell responses. This results in: (1) cochlear
vascular injury due to immune complex deposition, (2)
autoantibody-related microthrombosis and (3) vascular changes involving
electrochemical disturbances and impaired neurosignalling.[2]
When the inner ear is the only organ affected, AIED is considered
‘primary’. If it occurs with systemic autoimmune diseases such as
systemic lupus erythematosus, rheumatoid arthritis and Sjogren’s
syndrome, it is considered ‘secondary’. Secondary AIED accounts for up
to 30% of cases. [2] The Harris AIED
classification [7] further categorises the
condition into 6 different types. Our patient’s condition co-exists with
UC and is classified as secondary AIED, or ‘type 2: rapidly progressive
bilateral SNHL with systemic autoimmune disease.’[7]
There is a lack of standardised diagnostic criteria and pathognomonic
tests for AIED so diagnosis can be challenging and is often based on
exclusion. Diagnosis typically relies on 3 factors: clinical evaluation,
blood tests and response to corticosteroids. [2,
7] Laboratory tests must be conducted in all patients with suspected
AIED. This includes routine blood tests and autoimmune screening (Figure
1) to investigate for underlying systemic autoimmune disease and exclude
other differential diagnoses. [2] There are no
confirmed serological markers, but a few have been proposed such as heat
shock protein 70 (HSP70) antibody, an autoantibody that targets an inner
ear antigen. [8] It was thought to be a predictor
of steroid responsiveness but in a further study, it was found to be
insufficiently sensitive to detect AIED and lacked specificity to
predict steroid responsiveness. [5, 7] A response
to corticosteroids is defined as meeting these 2 requirements: (1)
improvement in SNHL >15 dB at any frequency OR >10
dB in at least 2 consecutive frequencies OR an increase in
pure-tone air conduction threshold loss at any frequency or decrease in
WRS. [2, 7] MRI also plays a role in the diagnosis
to rule out retrocochlear pathologies. [2]
The clinical features of AIED can mimic other inner ear pathologies such
as sudden sensorineural hearing loss (SSHL) and Meniere’s disease (MD),[2, 8] and may often be misdiagnosed. It can be
differentiated by observing the timing of disease onset; for example,
hearing loss in SSHL is characterised by an acute onset of <3
days and in MD, this typically occurs over years.[2] A case report by Ho et al. [2016]
discussed a patient with AIED presenting as MD [8]who, after 4 years of symptom onset, presented with psoriasis, joint
pains and anterior uveitis. It was then that a diagnosis of AIED was
suspected. The patient was started on a trial of corticosteroids, which
he responded to, and was switched to steroid-sparing therapy.[9] In our patient’s case, he was initially
diagnosed with bilateral labyrinthitis following his unremarkable MRI
and blood test results. The diagnosis of AIED was considered
approximately 5 weeks after his initial presentation after he
re-presented multiple times with a deterioration in his hearing shortly
after finishing his course of steroids. However, it took almost 1 year
from his initial presentation and referral to an ENT specialist that
undertook cortical evoked response audiometry to definitively confirm
the diagnosis of AIED.
AIED is one of the few forms of SNHL which may be reversible so prompt
medical management is crucial as it may improve the rates of reversing
hearing loss. [4] The patients in McCabe’s study
in 1979 were initially treated with cyclophosphamide and corticosteroids[1] however due to the substantial risks
associated with long-term cyclophosphamide use, including malignancy and
myelosuppression, most clinicians favoured high-dose prednisolone (60mg
OD) as the primary treatment for AIED. [6]High-dose steroid use is also associated with health risks and adverse
effects [6] such as hyperglycaemia, weight gain
and fractures secondary to osteoporosis. A study found that with good
patient education and monitoring, it is a safe and effective treatment
for AIED [10] but is not effective for
long-lasting management and is associated with episodes of relapse.[11]
Although corticosteroids remain the mainstay treatment, there are
varying levels of steroid-responsiveness initially and throughout the
treatment. One study evaluating the efficacy of AIED treatment reported
that the overall patient response rate to oral prednisolone was 69.7%.[6, 7] Another study found that only 14% remain
corticosteroid-responsive after 34 months, most notably in those who
present with repetitive deterioration in hearing requiring
corticosteroid treatment. [6] Our patient received
numerous courses of steroids during this treatment process and initially
saw an improvement in his symptoms with prednisolone 40mg OD later
required 60mg OD to get the same response. He would also experience a
worsening of his symptoms when he is on lower doses or off steroids,
relapsing as early as 3 days after stopping treatment.
There is a risk of further decline in hearing in the absence of therapy
and yet, there is no standard treatment protocol for AIED following
corticosteroids as randomised controlled trials (RCTs) are limited.[7] Studies regarding alternative steroid-sparing
therapies have yielded variable results, with much of the data relying
on case reports and case series. [3, 11]Alternative therapies that have been trialled include methotrexate,
azathioprine and immunomodulators [11] such as
biologics, including TNFα inhibitors (etanercept and infliximab), CD20
inhibitors (rituximab) and IL-1 inhibitors (anakinra and canakinumab).
If medical treatment fails and hearing is lost, cochlear implantation is
an effective treatment option for these patients.[4]
The efficacy of methotrexate was assessed in a multicentre clinical
trial as a potential steroid sparing therapy in
corticosteroid-responsive patients but did not demonstrate a greater
effect than the placebo. [5] A case report
described a presentation of relapsing AIED in a 35-year-old woman who
had a significant response to methotrexate and azathioprine dual
therapy. This combination yielded positive outcomes and was
well-tolerated. [12] Our patient was initially
tried on methotrexate in combination with azathioprine which he was
already taking for his UC but unfortunately showed little to no
improvement.
Our patient’s AIED is classified as secondary and more specifically, it
fits the Harris AIED classification type 2 that often worsens with flare
of the autoimmune condition. This type is steroid-responsive and can be
managed with targeted therapies that are effective against their
underlying condition. [7] The AIED specialist
centre and gastroenterology agreed that AIED is a rare manifestation or
complication of UC. This, combined with the failure of achieving
remission for his UC despite being on azathioprine and receiving
multiple courses of high-dose steroids, led the MDT to commence him on
infliximab. The patient showed clinical and audiometric improvement
after two loading doses of infliximab infusions. His hearing remained
stable, and he also reported improvement in his bowel habits and
symptoms of UC since starting therapy. The patient has tolerated
infliximab well and has remained on the infusions.
On literature review, there are two similar case reports to our
patient’s presentation. One reported a case of a 49-year-old man with
AIED who was responsive to corticosteroids but experienced frequent
relapses and progressive deterioration of hearing. He was tried on
multiple agents, but these failed to stabilise his symptoms. After
receiving infliximab treatment, he was noted to have a sustained improve
in his hearing and tinnitus. There was an attempt to discontinue his
treatment after 46 weeks, but this led to a rapid relapse of his
condition, though his hearing quickly recovered after restarting
infliximab. [13] Another case report presented a
case of AIED in a patient with Crohn’s disease that showed improvement
to anti-TNFα therapy, halting the progression of hearing loss, as well
as improving hearing by an average of 15dB across all frequencies. The
patient’s hearing remained stable after. [14]
A pilot placebo-controlled study on anti-TNFα therapy, etanercept, in
AIED however resulted in a different outcome. [15]This involved 20 patients with AIED in a 12-week blinded
placebo-controlled RCT of subcutaneous etanercept 25mg twice weekly. The
efficacy of etanercept therapy failed to exceed the placebo response.
Another study on 8 patients with steroid-refractory AIED concluded that
systemic infliximab therapy did not improve hearing loss.[16]
Although studies on biologic therapy have variable results on hearing
improvement, they have shown benefits on treating other aural symptoms
such as ear fullness, vertigo and tinnitus, [8]with a retrospective study reporting that >80% of patients
demonstrated improvement in these symptoms on treatment with adalimumab
and rituximab. [7] Some studies involving
methotrexate have also demonstrated a similar result, with one reporting
an 80-100% improvement rate in vestibular symptoms.[9] Steroid-sparing therapy should therefore not
be eliminated based on lack of improvement in hearing alone.
The disparity in response could potentially be explained by factors such
as timing of the treatment relative to corticosteroid use, the type of
anti-TNFα therapy used, and route of administration.[5] The later adaptive immune responses in AIED
are often influenced by the early expression of cytokines during the
innate immune response, such as TNF. Elevated levels of TNF are
identified to be predictive of corticosteroid-responsiveness in AIED.
Experimental observations reveal that peripheral blood immune cells from
corticosteroid-responsive patients release high levels of TNF in vitro
and these are reduced significantly on administration of dexamethasone.
It is possible that the initial use of corticosteroids prior to
anti-TNFα administration causes an excessive reduction of the TNF
levels, potentially compromising its effectiveness in placebo-controlled
trials. [5]