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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.
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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
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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
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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
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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
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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.
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