WJM World Journal of

Methodology
Submit a Manuscript: http://www.wjgnet.com/esps/ World J Methodol 2014 June 26; 4(2): 91-98
Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 2222-0682 (online)
DOI: 10.5662/wjm.v4.i2.91 © 2014 Baishideng Publishing Group Inc. All rights reserved.

REVIEW

New prospects in the diagnosis and treatment of

immune-mediated inner ear disease

David R Lobo, Jose Ramon García-Berrocal, Rafael Ramírez-Camacho

David R Lobo, Department of Otolaryngology, Hospital El Esco- therapy may have a role in the future. The intratym-
rial, San Lorenzo de El Escorial, 28200 Madrid, Spain panic route of administration avoids the systemic side
David R Lobo, Instituto Antolí-Candela, 28043 Madrid, Spain effects associated with currently used drugs, and may
Jose Ramon García-Berrocal, Rafael Ramírez-Camacho, become a more frequent approach in the future.
Department of Otorhinolaryngology, Hospital Puerta de Hierro,
Majadahonda, 28222 Madrid, Spain
© 2014 Baishideng Publishing Group Inc. All rights reserved.
Author contributions: Lobo DR, García-Berrocal JR and
Ramirez-Camacho R solely contributed to this paper.
Correspondence to: David R Lobo, MD, PhD, Department of Key words: Autoimmune inner ear disease; Diagnostic
Otolaryngology, Hospital E Escorial, Carretera Guadarrama s/n, tests; Biologic therapy agents; Gene therapy; Stem
San Lorenzo de El Escorial, 28200 Madrid, cells
Spain. dlobo28@gmail.com
Telephone: +34-918-973021 Fax: +34-918-973031 Core tip: Readers interested in inner ear pathology will
Received: November 26, 2013 Revised: February 10, 2014 find in this review a brief summary of autoimmune
Accepted: April 11, 2014 inner ear disease, with special focus on the major ad-
Published online: June 26, 2014 vances achieved in the knowledge of its etiology and
pathophysiology, and the diagnostic and therapeutic
challenges that remain and may guide research in the
next few years and beyond.
Abstract
Autoimmune inner ear disease (AIED) represents a
very fertile research field and the advancements in the Lobo DR, García-Berrocal JR, Ramirez-Camacho R. New pros-
understanding of this disease have a direct application pects in the diagnosis and treatment of immune-mediated inner
not only in patients affected with this condition but also ear disease. World J Methodol 2014; 4(2): 91-98 Available from:
in other inner ear disorders that share the same injury URL: http://www.wjgnet.com/2222-0682/full/v4/i2/91.htm DOI:
mechanism, damage to the inner ear hair cells. AIED http://dx.doi.org/10.5662/wjm.v4.i2.91
also presents many challenges that have still to be
overcome. Firstly, access to the inner ear is limited, as
many interventions such as biopsies can result in great
irreversible damage. Secondly, there are no completely INTRODUCTION
specific markers for AIED. Lack of a definitive diagno-
In 1979, Brian McCabe proposed a new clinical entity
sis can result in the treatment of patients not affected
which he called autoimmune sensorineural hearing loss
with the disease and, therefore, no response. Finally,
some patients become refractory to glucocorticoids
on the basis of a clinical and diagnostic study of a series
and new therapies are needed. This review offers an of 18 patients and the experience acquired in their treat-
overview of the animal models that have contributed to ment[1]. He defined the disease as a bilateral, generally
the understanding of AIED pathophysiology, the value asymmetric hearing loss that progresses in the course of
of currently available diagnostic tests, and therapeutic weeks or months and responds to immunosuppressive
options, with a special focus on new therapies for non therapy. This last characteristic is essential because this
responders or patients refractory to glucocorticoids. disease is one of the few forms of sensorineural hearing
Among these new options for therapy, biological agents loss potentially reversible with medical treatment.
have been tested recently, whereas gene and stem cell The concept of autoimmunity was not fully accepted

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 Lobo DR et al . Major advances in AIED

by the scientific community until the late fifties and early antibody complex deposits in the inner ear because the
sixties. Autoimmunity is defined as an immune reaction inner ear cannot be biopsied, although this evidence can
against the body’s own antigens. Although the etiology of be detected in animal models.
autoimmune inner ear disease (AIED) is not well known, The main animal models that have contributed to the
several etiopathogenic mechanisms that could explain understanding of the pathophysiology of AIED are as
this autoimmune reaction are similar to those giving rise follows.
to other autoimmune diseases. These mechanisms involve
autoreactive CD4+ T cells. However, there is another Model of experimental labyrinthitis by means of
group of diseases, called autoinflammatory diseases, in homologous or heterologous sera against cochlear
which the chronic inflammatory reaction is not mediated tissues
by T cells. This group includes Muckle-Wells syndrome, This was the first animal model ever employed to study
which presents clinical features similar to those of other inner ear autoimmunity[6]. The results obtained have been
autoimmune diseases, and may cause sensorineural hear- variable, ranging from non-histopathological changes
ing loss, but this does not respond to corticosteroids and to the development of endolymphatic hydrops, edema,
a genetic origin has been proposed[2]. The involvement hemorrhage, or perivascular inflammatory infiltrates. This
of CD4+ T cells is because not all autoreactive T cells are model employs an inner ear homogenate and cannot,
eliminated in the thymus. While this elimination process therefore, characterize specific autoantigens involved in
is efficient with most antigens expressed in the human the development of AIED[7].
body, this is not the case with the less frequent antigens,
such as those expressed in the inner ear. Fortunately there Model of experimental labyrinthitis by transferring
are other regulatory mechanisms that prevent the activa-
activated T lymphocytes
tion of these T lymphocytes.
The activation of T lymphocytes is achieved by employ-
The autoimmune reaction in AIED could be initiated
ing both inner ear homogenates and specific peptides
by an autoimmune attack when the immune system tries
such as cochlin, which is highly expressed in the inner
to protect the inner ear against infection or external in-
ear, or beta-tectorin[8-10].
sult[3]. Viruses or pathogenic bacteria can reach the inner
ear from the bloodstream, cerebrospinal fluid or middle
ear and could contribute to the autoimmune response Model of experimental labyrinthitis by autoantibodies
by altering host molecules so that they become self-an- Monoclonal autoantibodies against inner ear cells have
tigens[4]. Lesions caused by surgery, trauma or drugs can been generated by immunizing mice with guinea pig or
expose inner ear antigens to the immune system, thereby chicken inner ear extracts. KHRI-3 binds to the support-
inducing an immune response against both ears. More- ing cells in the organ of Corti causing hearing loss in
over, these insults can result in permanent tissue damage guinea pigs[11]. The lack of infiltrates suggests that the le-
which can trigger an immune response in the future. sions of the stria vascularis, spiral ligament or supporting
According to the revised Witebsky postulates pro- cells are mediated by antibodies or immune complexes[12].
posed by Rose et al[5], there are three levels of evidence
of an autoimmune disease: direct, indirect and circum- Model of experimental labyrinthitis by keyhole limpet
stantial. Direct evidence requires the transmission of hemocyanin
the characteristic lesions from human to human or from This model was developed by Harris and coworkers and
human to animal. This could occur, for instance, if the has contributed greatly to the knowledge of AIED patho-
clinical features are reproduced in newborns from moth- physiology. The endolymphatic sac contains immune sys-
ers with AIED, or in animals after injecting them with tem cells capable of inducing or reinforcing an immune re-
antibodies detected in AIED patients. However, in AIED sponse[13]. The spiral vein of modiolus is the entryway for
most of the evidence is indirect or circumstantial. Indi- immunologic elements (T cells, B cells, natural killer (NK)
rect evidence is based on the re-creation of the human cells, polymorphonuclear cells, macrophages) that can in-
disease in an animal model by transferring antibodies or duce a labyrinthitis that results in functional impairment
autoimmune T cells, or on the use of animal models of with loss of sensorial cells and ultimately leads to cochlear
multisystem autoimmune disease. Circumstantial evidence fibrosis and osteoneogenesis (Figure 1)[14,15].
found in AIED includes a family history of autoimmune
disease, coexistence with other autoimmune diseases
(such as systemic lupus erythematosus, Behçet’s disease,
EPIDEMIOLOGY
Wegener granulomatosis, relapsing polychondritis among The incidence of AIED is not well-known because there
others), predominance of certain major histocompat- is no definitive diagnostic test. Nevertheless, it is consid-
ibility complex alleles (DR4-, cw7+, cw4+, B35), raised ered to be less frequent than sudden deafness, with 1 case
immunoglobulin G antibodies titers, and clinical response out of 5000-10000 people per year. Like other autoim-
to immunosuppressive therapy. In AIED patients it is im- mune diseases, it appears to be more frequent in women.
possible to obtain other circumstantial evidence such as It generally presents between the ages of 20 to 50 years,
the presence of mononuclear cell infiltrate or of antigen- and it is uncommon in childhood[16].

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 Lobo DR et al . Major advances in AIED

KLH injection in the scala tympani

Antigen presenting cells (macrophages)

3h

TNF-α and TGF-β secretion

6h
IL-1 secretion

Transformation of the spiral Recruitment of PMN, monocytes and lymphocytes

modiolar vein (peripheral blood and endolymphatic sac)
6-12 h
Expression of adhesion Anti-KLH antibodies, deposit of
IL-1, IL-6 and TNF-α
molecules (ICAM-1, immune complexes in the spiral
expression
VCAM-1, selectin-L, ligament, stria vascularis and
integrin α4) endolymphatic sac

Extravasation of leukocytes to the scala Dysfunction of type Ⅱ fibrocytes and

tympani supporting cells

Formation of fibrous matrix and granuloma +

Alteration of K homeostasis

Osteoneogenesis and apoptosis of

inflammatory cells
4-5 wk
Cochleovestibular damage (organ of Corti degeneration, endolymphatic hydrops)

Figure 1 Immunopathological sequence in experimental labyrinthitis by keyhole limpet hemocyanin. KLH: Keyhole limpet hemocyanin; TNF-α: Tumor ne-
crosis factor alpha; TGF-β: Transforming growth factor beta; IL-1: Interleukin 1; PMN: Polimorphonuclear cells; ICAM-1: Intercellular adhesion molecule 1; VCAM-1:
Vascular cellular adhesion molecule 1.

CLINICAL PRESENTATION ear biopsy represents the destruction of the organ and its
function.
AIED can present alone or associated with other autoim- The diagnosis of AIED is based fundamentally on
mune systemic disease (secondary AIED). Generally, three clinical evaluation, the demonstration of a progressive
forms of clinical presentation are recognized: sudden sensorineural hearing loss in periodic audiological tests
deafness, rapidly progressive hearing loss, and fluctuating and a response to immunomodulatory drugs such as cor-
hearing loss. Vertigo appears in almost 50% of cases, mak- ticosteroids.
ing AIED difficult to distinguish from Meniere’s disease[17]. Once other causes of sensorineural hearing loss
Eventually, AIED can affect both ears and progress to have been ruled out, patients undergo a battery of non-
deafness unless a correct diagnosis is made and prompt specific test common to other autoimmune diseases:
treatment is established. Since this clinical picture is not blood tests, biochemistry, erythrocyte sedimentation rate,
specific, and could cover almost all inner ear disorders, etc. In certain cases, serological studies can detect some
diagnostic criteria are needed to orientate the introduc- specific autoantibodies, but there are no immunological
tion of medical treatment. or serological tests that are specific or sensitive enough to
establish a definitive diagnosis[18]. A summary of the main
specific and non-specific autoantibodies found in AIED
DIAGNOSIS patients and experimental models is given in Table 1.
A prompt diagnosis and treatment has a great impact on Most studies deal with one or several autoantibodies and
the hearing prognosis of patients with AIED and thus no single study has examined them all in the same popu-
has stimulated the search for specific markers of inner lation.
ear inflammation. The presence of autoantibodies is usu-
ally the first step in recognizing the autoimmune nature Immunological tests
of a disease, but this is not enough as autoantibodies are Numerous tests have been proposed, antibodies against
also common in people without an autoimmune disease. collagen type II, endothelial cells, sulfoglucoronosyl gly-
In fact, autoantibodies against specific cochlear antigens colipids, major peripheral protein P0, etc (Table 1). The
have a low specificity for rapidly progressive sensorineu- role of immune complexes and changes in blood lym-
ral hearing loss. Although other localized autoimmune phocytic populations has also been studied[19].
diseases such as pemphigus or cutaneous vasculitis are
diagnosed by immunofluorescence in biopsied tissues, Western blot
this is not possible in the case of AIED because an inner Harris and Sharp proposed this technique to identify spe-

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 Lobo DR et al . Major advances in AIED

Table 1 Specific and non-specific autoantibodies present in Table 2 Diagnostic profile for autoimmune inner ear disease
autoimmune inner ear disease patients and/or animal models
of sterile labyrinthitis Major criteria
Bilateral hearing loss
Specific autoantibodies Systemic autoimmune disease
Collagen type Ⅱ ANA > 1:80
Collagen type IX Decrease of native T cells (CD4CD45RA)
Cochlin Hearing recovery rate > 80%
DEP-1/CD 148 Minor criteria
KHRI-3 Unilateral hearing loss
Myelin protein P0 Young or middle aged
Raf-1 Woman
Beta-tectorin Hearing recovery rate < 80%
Beta-actin
Connexin 26 Hearing recovery rate (after immunosuppressive therapy) is obtained: (ini-
Non-specific autoantibodies tial hearing levels - final hearing levels)/initial hearing level – opposite ear
Antinuclear antibodies hearing levels) × 100 (%). An autoimmune inner ear disease is suspected
Anti-neutrophil cytoplasmic antibodies when three major criteria or two major and two minor criteria are met.
Anti-endothelial cell antibodies
Rheumatoid factor
Heat shock protein of 70 kDa for a month. Shorter courses or lower doses have proved
Anti-phospholipids/anticardiolipin antibodies to be ineffective and increase the risk of relapse[24]. In
Antithyroid antibodies
rapidly progressive forms 1 mg/kg per day is maintained
for 4 wk until the audiogram is stable and the dose is
then tapered over 8 wk to 10-20 mg per day, which is
cific autoantibodies against inner ear antigens in immu- maintained for another 6 wk. In cases of sudden hear-
nized animals and in patients with sensorineural hearing ing loss, 1 mg/kg per day of 6-methylprednisolone is
loss[20]. Among these autoantibodies, the most studied is administered for four weeks. In severe hearing loss (over
an antibody that binds to a 68 kD antigen derived from a 70 dB) three pulses of 500 mg are administered, and then
bovine temporal bone extract and the inducible form of the above-mentioned dosage regimen is applied. When
heat shock protein 70 (HSP-70)[21]. HSP-70 is expressed patients receive high doses of corticosteroids, active tu-
in a variety of pathological inner ear conditions, as a berculosis must be ruled out, and glycemia, potassium
marker of early cell damage, but is not specific. In AIED and blood pressure must be monitored. Tapering must
patients, the frequency of antibodies against HSP-70 is be gradual, slower if glucocorticoids have been given at
not different in patients and controls and is not useful in higher doses or for a longer time.
the diagnosis of AIED[22]. Mice immunized with HSP-70 In AIED patients, severe adverse reactions have rarely
produce anti HSP-70 antibodies without presenting a been reported (0%-0.9%) though they may be more
hearing loss, which indicates that these antibodies are not frequent when high dose intravenous pulse corticoste-
directly involved in the pathogenesis of AIED. However, roids are employed. The overall rate of side effects is not
these antibodies could have a role as markers of disease greater than 7.8%[25].
activity and treatment response.
Other immunosuppressants
Imaging studies Some patients do not respond to corticoids or require
Neither magnetic resonance imaging (MRI) nor positron high doses to control the disease, and other immunosup-
emission tomography (PET) has demonstrated their utility pressants such as methotrexate or cyclophosphamide
in the diagnosis of AIED in spite of early promising results. have been tried. The empirical basis for using these
drugs is the observation that in certain cases their effect
Diagnostic profiles enhances that of the corticosteroids, thus obtaining re-
Although specific tests have an unquestionable value, mission of one or more symptoms that is not achieved
there is no currently available test that has proved to be with corticosteroids alone, or allowing reduction of the
effective. For this reason, the development of diagnostic required dose of corticosteroids to maintain the patient
profiles can contribute to cost saving by restricting the di- symptom-free.
agnostic tests to those which are really cost-effective[23]. A
proposed diagnostic profile for AIED is shown in Table 2. Methotrexate: A meta-analysis showed that there was no
An AIED is suspected when three major criteria or two benefit with methotrexate compared with corticosteroids
major and two minor criteria are met. alone[26]. However, vertigo or instability can improve with
long treatments.
The most frequently employed regimen is 7.5 mg
TREATMENT weekly administered in one single dose. Once the re-
The treatment most widely used for AIED is corticoste- sponse is achieved, the drug is given orally (15 mg
roids therapy. The initial dosage regimen is 60 mg or 1 weekly) for 12 mo. Methotrexate is associated with blood
mg/kg per day of prednisone or 6-methylprednisolone toxicity (leukopenia, thrombocytopenia), liver toxicity

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 Lobo DR et al . Major advances in AIED

Table 3 Biological therapy agents

Drug Anti Dosage Licensed indications EMA approval FDA approval

Etanercept TNF-a 25 mg × 2/wk or 50 mg/wk sc RA, JRA, PsA, AS, Ps 2000 1998
Infliximab TNF-a 3 mg/kg at 0, 2 and 6 wk followed by 3.5-7.5 mg/8 wk iv RA, PsA, AS, Ps, UC, CD 1999 1998
Adalimumab TNF-a 40 mg/1-2 wk sc RA, JRA, PsA, AS, Ps, CD 2003 2002
Anakinra IL-1 100 mg/d sc NHL, CLL, RA 2002 2001
Rituximab B-cell CD20R 1 g/wk × 2 iv RA 1998 1997

Dosage and indications approved by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). RA: Rheumatoid
arthritis; JRA: Juvenile rheumatoid arthritis; PsA: Psoriatic arthritis; AS: Ankylosing spondylitis; Ps: Psoriasis; UC: Ulcerative colitis; CD: Crohn´s disease;
NHL: Non-Hodgkin lymphoma; CLL: Chronic lymphocytic leukemia.

(elevated liver enzymes, periportal fibrosis, cirrhosis) and tympanic route.

gastrointestinal toxicity (nausea, vomiting, mucositis). Fo-
lic acid supplements reduce the adverse effects, preserve Intratympanic therapy
its efficacy and are, therefore, recommended. The use of intratympanic corticosteroids is an attractive
therapeutic approach because it is minimally invasive and,
Cyclophosphamide: This drug was used by McCabe[1], since the drug is applied directly to the affected ear, side
who advocated its use as the treatment of choice, in his effects are minimized. However, there is no consensus
original series of cases. However, because of its adverse regarding the doses and length of treatment. Moreover, it
effect profile (gonadal, bladder and bone marrow toxicity) is not easy to control the dose that actually enters the in-
it is not frequently used and is limited to those patients ner ear (part of it is absorbed in the middle ear and part
who do not respond to corticosteroids or do not main- is eliminated through the Eustachian tube); as a result, its
tain their response after dose tapering. The oral dose is efficacy has so far not been fully determined[28].
1-2 mg/kg per day for 4-6 wk. Intravenously, the starting
dose is 0.75 g/m2 or 0.5 g/m2 if the glomerular filtration Biological therapy agents
rate is lower than a third of the normal value, and this is Biological therapy agents are fusion proteins (made from
repeated every 1-3 mo. The white cell count should not a fusion gene, which is created by joining parts of two or
be lower than 2000/mm3 and neutrophils should remain more genes) or monoclonal antibodies designed to block
over 1000/mm3. When both cyclophosphamide and high specific components of the inflammatory cascade. Tu-
doses of corticosteroids are employed trimethoprim/sul- mor necrosis factor α inhibitors and lymphocyte CD20
phamethoxazole or dapsone is administered to prevent receptor antagonists have recently been tested on AIED
Pneumocystis carinii pneumonia. patients (Table 3).
Among the biological therapy agents the most fre-
Plasmapheresis quently used are tumor necrosis factor alpha blockers.
This procedure allows the blood to be separated into its Tumor necrosis factor (TNF) is a proinflammatory cyto-
two components - blood cells and plasma - and allows kine produced by multiple cells, especially macrophages,
some components such as antibodies to be removed that stimulates the maturation and migration of dendritic
before the cells and plasma are transfused back to the pa- cells, activates neutrophils and NK cells, and increases
tient. In a long term study performed in AIED, 50% of vascular permeability. It was isolated by Carswell et al[29]
the patients achieved an improvement or stabilization of in 1975 when they were seeking to identify the factors
hearing loss after this therapy[27]. responsible for Meth A sarcoma necrosis. It is expressed
early in the inflammatory response in different inner ear
structures. Of the different TNF-α blockers that have
NOVELTIES IN AIED THERAPY been developed, etanercept, infliximab and adalimumab
The overall response rate to corticosteroids is 60%, but have been tested on AIED patients. X-ray or Mantoux
the response rate varies considerably. In most responders screening is recommended before initiating treatment
the dose can be lowered or corticosteroids can be with- with TNF-α blockers because TNF-α is a key compo-
drawn without relapse, but some patients can present a nent in the body’s defense against M. tuberculosis and other
corticosteroid-dependant hearing loss. Hearing loss may granulomatous diseases.
become refractory to corticosteroids, and other immuno-
suppressants should be considered in these cases. Finally, Etanercept: The results obtained so far are promising
treatment can result in unacceptable adverse reactions but not conclusive, as very few studies have been per-
(gastritis, peptic ulcer, fluid retention, glucose intolerance, formed[30]. Anecdotically, it has been used together with
avascular necrosis of the femoral head, psychiatric prob- methotrexate with good results, allowing corticosteroid
lems, sleep disorders, cataracts, osteoporosis, cushingoid therapy to be withdrawn[31]. The usual dose is 25 mg
habitus) and this has prompted the search for new drugs administered by subcutaneous injection twice a week or
or different modes of administration such as the intra- 50 mg once a week for an indefinite period of time. Side

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 Lobo DR et al . Major advances in AIED

effects that have been a concern are infections including which would attempt to repair established damage to
tuberculosis and sepsis, tumors such as lymphomas, ane- the inner ear. These therapeutic strategies are based on
mia and pancytopenia, demyelinating diseases, congestive the knowledge of cell signaling routes involved in the
heart failure and hypersensitivity. However, a meta-anal- development of the cochlear sensorial epithelium during
ysis that examined the adverse reactions with etanercept embryogenesis. This sensorial epithelium derives from a
and other biologic therapies in 163 randomized con- group of cells that after several divisions start to differen-
trolled studies with 50010 participants and 46 extension tiate into hair cells and supporting cells. Adult mammals
studies with 11954 participants reported that the severe have lost the capacity to regenerate damaged hair cells[38].
adverse reactions rate for the biological products was not Gene and stem cell therapy attempt to revert this situa-
different from that of the control therapy (e.g., corticoste- tion[39]. However, both approaches present the same haz-
roids)[32]. ards and difficulties: access to the whole cochlea, integra-
tion and maturation of hair cells in the correct position
Adalimumab: It is administered by a subcutaneous in- within the cochlea and not in ectopic locations, and risk
jection of 40 mg every two weeks for an indefinite period of tumor development[40]. At present, these difficulties
of time. The dose can be increased to 40 mg weekly if need to be overcome before clinical trials can be started.
a decrease in the response is observed. It has been em-
ployed successfully in one patient with autoimmune sen-
sorineural hearing loss and rheumatoid arthritis[33]. CONCLUSION
Different animal models of experimental labyrinthitis
Infliximab: The usual regimen is slow intravenous infu- have contributed to the understanding of AIED patho-
sion (2 h) of 3 mg/kg at the start of treatment, and at 2 physiology. In particular, the model of experimental laby-
and 6 wk, followed by maintenance therapy every 8 wk rinthitis by KLH has allowed a chronological sequence
indefinitely. Intratympanic administration of infliximab of inner ear damage to be established and has, therefore,
can help to reduce corticosteroids doses in patients with provided a rational basis for testing new therapies.
AIED[34]. In spite of all the efforts to find a good marker for
the disease, the available tests are not specific or sensitive
B lymphocyte CD20 receptor antagonist: Apart from enough to establish a definitive diagnosis. However, the
TNF-α blockers other biological therapy agents such search for specific autoantibodies for AIED remains a
as rituximab have been recently tested on patients with valid approach, because the diagnostic value of autoanti-
AIED. Rituximab is a chimeric monoclonal antibody that bodies depends on a statistical and epidemiological asso-
binds to the CD20 receptor of B lymphocytes, thereby ciation with disease more than on a cause-effect relation.
inducing apoptosis and reducing their number. The few It would be very useful to study how these autoantibody
studies that have used rituximab in AIED patients have titers vary with time and with response to therapy. More-
yielded encouraging results[35,36]. However, more studies over, some autoantibodies could provide information on
are needed for reliable conclusions to be reached. The group of patients with different prognoses or different
recommended dose is 1000 mg in intravenous injection, clinical responses.
followed by a second injection perfusion of 1000 mg 2 Finally, new treatments have been tested recently.
wk later. The most common side effect associated with Biologics, a new family of immunomodulatory agents,
rituximab is a reaction to the injection (low blood pres- could play a role in the treatment of AIED in the future,
sure, nausea, eruption, fever, itching, urticaria, throat ir- and the first studies conducted with these drugs have
ritation, tachycardia, peripheral edema). Infections of the produced promising results. They could be indicated in
upper airway and urinary tract have also been reported patients who do not respond to, or who have become
(but not in AIED patients). refractory to, glucocorticoids. However, more clinical
studies are necessary to evaluate their real value. Intra-
Future possibilities in AIED therapy tympanic therapy avoids many of the adverse reactions
Anakinra is an IL-1 inhibitor that has been successfully associated with currently used drugs, but this approach
used in chronic infantile neurological cutaneous and ar- has not been sufficiently evaluated yet.
ticular (CINCA) syndrome and Muckle-Wells syndrome,
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P- Reviewer: Hong YR, Schuurman HJ S- Editor: Wen LL

L- Editor: A E- Editor: Wu HL

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