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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
Servicio de Otorrinolaringología, Hospital El Escorial, Universidad Francisco de Vitoria, San Lorenzo de El Escorial, Madrid, Spain
b
Servicio de Otorrinolaringología, Hospital Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, Spain

Received 26 February 2012; accepted 23 April 2012

KEYWORDS Abstract
Immune-mediated Introduction and objectives: Immune-mediated inner ear disease (IMIED) is one of the few
inner ear disease; reversible forms of sensorineural hearing loss. Treatment is based on high-dose corticosteroids,
Biological agents; although long-term therapy is associated with serious adverse effects; this has led to the use
Etanercept; of other agents or different routes of administration such as transtympanic delivery. This study
Tumour necrosis analyses the role of biological agents in IMIED management.
factor ␣; Material and methods: We searched PUBMED for studies that examined the response to treat-
Anakinra; ment with different biological agents in patients with IMIED. The following data were extracted
Rituximab 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, inflix-
imab, 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: dlobo28@gmail.com (D. Lobo).

2173-5735/$ – see front matter © 2012 Elsevier España, S.L. All rights reserved.
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224 D. Lobo et al.

PALABRAS CLAVE Revisión de las terapias biológicas en la enfermedad inmunomediada del oído interno
Enfermedad
Resumen
inmunomediada
Introducción y objetivos: La enfermedad inmunomediada del oído interno (EIOI) es una de las
del oído interno;
escasas afecciones del oído interno que pueden revertirse con tratamiento médico. Este se
Terapias biológicas;
basa en los corticoides, si bien el tratamiento prolongado con los mismos se asocia a serios
Etanercept;
efectos adversos, lo que ha propiciado el uso de otros fármacos o vías de administración como
Factor de necrosis
la intratimpánica. En este estudio se analiza el papel de las terapias biológicas en el tratamiento
tumoral ␣;
de la EIOI.
Anakinra;
Material y métodos: Se ha realizado una búsqueda sistemática en PUBMED de aquellos estu-
Rituximab
dios 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 estabi-
lización. Sin embargo, son necesarios más estudios controlados y aleatorizados para conocer su
eficacia.
© 2012 Elsevier España, S.L. Todos los derechos reservados.

Introduction Specifically, we have studied the role of some tumour

Current knowledge of immune-mediated inner ear disease
(IMIED)1 assumes the possibility of interfering in its evo-
lution by stopping its progression and even improving the
function of the affected organ through the use of anti-
inflammatory 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 diag-
nosis 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 effi-
cacy 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 thera-
pies in the treatment of IMIED. Biological agents are fusion
proteins or monoclonal antibodies created to block spe-
cific 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
necrosis factor (TNF) inhibitors, such as etanercept, inflix-
imab 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 pro-
duced 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 ther-
apies 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, infan-
tile, neurological, cutaneous, and articular) syndrome. They
present clinical symptoms similar to those of some systemic
autoimmune diseases; however, they do not respond to cor-
ticosteroids 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 bio-
logical therapies in patients with IMIED. Secondarily, we
included those studies which analysed the response to bio-
logical therapies in patients with sensorineural hearing loss
secondary to other autoimmune or autoinflammatory dis-
eases.
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 225

Antagonist’’ OR (‘‘Antirheumatic agents’’ [pharmacological
action] AND (‘‘Hearing loss, Sensorineural’’ [Mesh]. Like-
wise, 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 crite-
ria 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 clar-
ity, studies were grouped into 3 different treatment groups.
TNF-␣ Inhibitors (Etanercept, Adalimumab, and
Infliximab)
These agents act by binding to soluble TNF or receptor-
bound 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 dis-
ease. 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 unilat-
eral hearing loss or taking into account the results of
otoblot® (antibodies against the 68 kDa protein), and exclud-
ing patients with systemic inflammatory diseases, such
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
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 monother-
apy 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 dis-
ease (CINCA, Muckle---Wells syndrome) (Table 2).20---22
All 3 studies consisted of clinical case report presenta-
tions.
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-year-
old female who obtained an improvement of 15---30 dB in the

Table 1 Response to Anti-TNF␣ (Etanercept, Infliximab, and Adalimumab).

First author Year Treatment Patients, Mean age, Stabilisation or Dosage and
n years improvement, % administration
route
Rahman et al.12 2001 Etanercept 12 47 91 25 mg × 2 every 7 days sc
Matteson et al.13 2005 Etanercept 23 48 87 Same
Cohen et al.14 2005 Etanercept 20 52 12.5 Same
Street et al.17 2006 Etanercept/ 1 56 100 25 mg × 2/w sc
methotrexate
Morovic Vergles et al.18 2010 Adalimumab 1 30 100 40 mg/w 12 w
Liu et al.15 2011 Infliximab 8 57 0 320---600 mg iv/4---12 w
Van Wijk et al.16 2006 Infliximab 9 51 77 0.3 ml/w 4 w transtympanic
Staecker and Lefebvre19 2002 Infliximab 1 35 100 NP
iv, intravenous; NP, not provided; sc, subcutaneous; w, week.
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226 D. Lobo et al.

Table 2 Response to Anakinra in Patients With Autoinflammatory Disease.

Rigante et al.20 Rynne et al.21 Gerard et al.22
Year 2006 2006 2007
Number of patients 1 1 1
Age 7 years 59 years 64 years
Percentage of improvement, % 100 0
Percentage of stabilisation, % 100
Autoinflammatory disease CINCA Muckle---Wells syndrome Muckle---Wells syndrome
Dosage 1 mg/kg/day Information not provided 100 mg/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 progres-
sive, 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.
Cohen et al.23
Year 2011
Number of patients 7 1
Mean age 47 years
Percentage of 71%
improvement
SAD 0 Cogan syndrome
Dose 1000 mg × 2 iv
iv, intravenous; SAD, systemic autoimmune disease.
treatment. Patients often respond to high doses of cor-
ticosteroids; 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 effi-
cacy in randomised, controlled clinical trials, whilst other
immunosuppressive treatments have shown excessive toxic-
ity, 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 autoim-
mune diseases, with a high efficacy and scarce adverse
effects.9,27,28 Biological agents are fusion proteins or mono-
clonal antibodies specifically created to block components
of the inflammatory cascade.
TNF inhibitors have been the most widely used biologi-
cal 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 neu-
trophils 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 struc-
tures 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. tuber-
culosis 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
Orsoni et al.24 corticosteroids.32,33
Other TNF inhibitors and biological agents have been
2010 developed since then. Table 4 shows these agents, together
with their mechanism of action. Fig. 1 shows the inflamma-
25 years tory cascade which leads to inner ear injury, showing where
100% the various biological agents studied intervene.
The percentages of improvement and stabilisation of
hearing achieved in many studies appear to support the role
500 mg iv/s 4 s 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 Remicade® Chimeric TNF␣ Binds to soluble and bound TNF 2463.52
Etanerceptb Enbrel® Humanised TNF␣ Competes with TNF receptors 1090
Adalimumabc Humira® Humanised TNF␣ Binds to TNF receptor 4510.28
Anakinra Kineret® Humanised IL-1 Antagonist of the IL-1 receptor 1944.24
Rituximab Mabthera® Chimeric CD 20 Binds to CD20 receptor of B lymphocytes 2899.15
a Chimeric human---mouse recombinant antibody, which binds to soluble and receptor-bound TNF.
b Dimer composed of the extracellular portion of 2 TNF␣ receptors and the Fc portion of human IgG1.
c Recombinant monoclonal antibody, formed by various human peptidic sequences.
d 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 Rah-
man 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. How-
ever, 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 sorineural hearing loss still needs to be elucidated. Given
B lymphocyte T cells (CD4RA, CD4RO)
Autoantibodies Lymphokines 3
IL12 IL1
NK, ADCC cells
Immunocomplexes
Th1 lymphocytes
IL2 TNF IF γ
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, progres-
sive 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 sen-
Monocyte
the small number of patients and the contradictory results,
macrophages it is not possible to draw conclusions from the articles
analysed. In the study by Gerard et al.,22 the patient pre-
Monokines sented a profound and established sensorineural hearing
IL4 IL13 loss, which could explain the lack of response to treat-
ment.
Although these results should be analysed with caution,
Th2 lymphocytes
they may be relevant to the implementation of prospective
studies.
IL4 IL10 IL13

1
Inner ear
lesion
Figure 1 Autoimmune mechanism suggested for IMIED. Num-
bers 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 cyto-
toxicity; 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 devel-
opment 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 immune-
mediated 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. Autoim-
mune 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. ORL J Otorhinolaryngol Relat Spec.
2008;70:271---4.
6. Harris JP, Weisman MH, Derebery JM, Espeland MA, Gantz
BJ, Gulya AJ, et al. Treatment of corticosteroid-responsive
autoimmune inner ear disease with methotrexate: a ran-
domized controlled trial. J Am Med Assoc. 2003;290:
1875---83.
7. García-Berrocal JR, Ibáñez A, Rodríguez A, González-García
JA, Verdaguer JM, Trinidad A, et al. Alternatives to systemic
steroid therapy for refractory immune-mediated inner ear dis-
ease: a physiopathologic approach. Eur Arch Otorhinolaryngol.
2006;263:977---82.
8. Herráiz C, Miguel Aparicio J, Plaza G. Intratympanic drug
delivery for the treatment of inner ear diseases. Acta Otorrin-
olaringol Esp. 2010;61:225---32.
9. Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleis-
chmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid
arthritis: a randomized, controlled trial. Ann Intern Med.
1999;130:478---86.
10. Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM.
Tumor necrosis factor-alpha, an initiator, and etanercept, an
inhibitor of cochlear inflammation. Laryngoscope. 2002;112:
1627---34.
11. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum
of clinical features in Muckle---Wells syndrome and response to
anakinra. Arthritis Rheum. 2004;50:607---12.
12. Rahman MU, Poe DS, Choi HK. Etanercept therapy for immune-
mediated cochleovestibular disorders: preliminary results in a
pilot study. Otol Neurotol. 2001;22:619---24.
13. Matteson EL, Choi HK, Poe DS, Wise C, Lowe VJ, McDonald TJ,
et al. Etanercept therapy for immune-mediated cochleovestibu-
lar disorders: a multicenter, open-label, pilot study. Arthritis
Rheum. 2005;53:337---42.
14. Cohen S, Shoup A, Weisman MH, Harris J. Etanercept treatment
for autoimmune inner ear disease: results of a pilot placebo-
controlled study. Otol Neurotol. 2005;26:903---7.
D. Lobo et al.
15. Liu YC, Rubin R, Sataloff RT. Treatment-refractory autoimmune
sensorineural hearing loss: response to infliximab. Ear Nose
Throat J. 2011;90:23---8.
16. Van Wijk F, Staecker H, Keithley E, Lefebvre PP. Local per-
fusion of the tumor necrosis factor alpha blocker infliximab to
the inner ear improves autoimmune neurosensory hearing loss.
Audiol Neurootol. 2006;11:357---65.
17. Street I, Jobanputra P, Proops DW. Etanercept, a tumor necro-
sis factor alpha receptor antagonist, and methotrexate in
acute sensorineural hearing loss. J Laryngol Otol. 2006;120:
1064---6.
18. Morovic Vergles J, Radic M, Kovacic J, Salamon L. Successful use
of adalimumab for treating rheumatoid arthritis with autoim-
mune sensorineural hearing loss: two birds with one stone.
J Rheumatol. 2010;37:1080---1.
19. Staecker H, Lefebvre PP. Autoimmune sensorineural hearing
loss improved by tumor necrosis factor-alpha blockade: a case
report. Acta Otolaryngol. 2002;112:1627---34.
20. Rigante D, Ansuini V, Caldarelli M, Bertoni B, La Torraca I, Sta-
bile A. Hydrocephalus in CINCA syndrome treated with anakinra.
Childs Nerv Syst. 2006;22:334---7.
21. Rynne M, Mclean C, Bybee A, Mc Dermott MF, Emery P. Hearing
improvement in a patient with variant Muckle---Wells syndrome
in response to interleukin 1 receptor antagonism. Ann Rheum
Dis. 2006;65:533---4.
22. Gerard S, le Gogg B, Maugars Y, Berthelot JM, Malard O.
Lasting remission of a Muckle---Wells syndrome with CIAS-1
mutation using half-dose anakinra. Joint Bone Spine. 2007;74:
659.
23. Cohen S, Roland P, Shoup A, Lowenstein M, Silverstein H,
Kavanaugh A, et al. A pilot study of rituximab in immune-
mediated inner ear disease. Audiol Neurootol. 2011;16:
214---21.
24. Orsoni JG, Laganà B, Rubino P, Zavota L, Bacciu S, Mora
P. Rituximab ameliorated severe hearing loss in Cogan’s
syndrome: a case report. Orphanet J Rare Dis. 2010;
5:18.
25. Lasak JM, Sataloff RT, Hawkshaw MJ, Carey TE, Lyons KM,
Spiegel JR. Autoimmune inner ear disease: steroid and cyto-
toxic drug therapy. Ear Nose Throat J. 2001;80:808---11, 815-6,
818 passim.
26. 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 etan-
ercept in patients with rheumatoid arthritis. J Rheumatol.
2001;28:1238---44.
28. Keystone E, Fleischmann R, Emery P, Furst DE, van Vollen-
hoven R, Bathon J, et al. Safety and efficacy of additional
courses of rituximab in patients with active rheumatoid arthri-
tis: 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 necro-
sis 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 endotoxin-
treatment. Brain Res. 1999;830:113---22.
32. Wang X, Truong T, Billings PB, Harris JP, Keithley EM. Block-
age of immune-mediated inner ear damage by etanercept. Otol
Neurotol. 2003;24:52---7.
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Review of the Biologic Agents Used for Immune-Mediated Inner ear Disease 229

33. Lobo D, Trinidad A, García-Berrocal JR, Verdaguer JM, Ramírez-
Camacho R. TNFalpha blockers do not improve the hearing
recovery obtained with glucocorticoid therapy in an autoim-
mune experimental labyrinthitis. Eur Arch Otorhinolaryngol.
2006;263:622---6.
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.