AUTOIMMUNE INNER

EAR DISEASE
McCabe BF. Ann Otol Rhinol Laryngeals 1979; 88:585

 Progressive (over weeks to months)

bilateral SNHL that responds to the
administration of immunosuppressive
agents
 Classification
 Primary
idiopathic pathology restricted to the ear
 Secondary
As part of a multisystemic, organ-
nonspecific autoimmune disease
 Pathogenesis
 Cross-reaction theory
Exposure to a harmful substance or infectious
agent leads to Ab production or T cell activation d/t
shared antigens

 Sympathetic cochleolabyrinthitis theory

infection, trauma (acoustic / physical / operative),
vascular damage of the inner ear protein
exposure lymphocytes sensitization
recirculate as memory lymphocytes
destruction of CL inner ear
 Animal Models

Buniel MC, Geelan-Hansen K, Weber PC, Tuohy VK. Immunotherapy. 2009;1(3):425-434.

 Autoantibodies
 1994, Mosciki: Anti-68kD antibody
89% patients with progressing bilateral hearing loss had Anti-
68kD antibody
Ab(+) patients: 75% response to steroid therapy, Ab(-): 18%

 1995, Billings, Bloch: Heat shock protein 70 (HSP 70)

Monoclonal Ab specific for HSP 70 binds the 68 kD antigen
Anti-68kD Ab binds to bovine HSP
 1999, Nair: KHRI-3 antibody
Mice carrying KHRI-3 antibody developed hearing loss
In guinea pigs, binding to supporting cell of organ of
Corti in a wine-glass pattern (IF)
Sera from AIED patients injected to guinea pigs ->
binding to supporting cell
KHRI-3 Ab binds to a 68-72-kD Ag on WB of inner ear
extract

 2004, Nair: Targets multiple peptides identical to

human ‘choline transporter-like protein 2’ (CTL2)
CTL2 coprecipitates cochlin, a protein critical to the
structure and function of the inner ear
 No direct evidence of HSP 70 are
immunopathogenic in AIED
 HSP 70 expression in other organs except
inner ear (kidney, intestine)

 Anti-68kD antibody targets CTL2 protein rather

than HSP 70??
KHRI-3?
anti- Re CS
68kD sp
on
ssi
v e

68kD
HSP? CTL-2?
 Clinical Features
 Rare disease (<1% of SNHL), F > M, 3rd-6th decades
 SNHL may be unilateral initially but becomes
bilateral within months (80%)
More rapid than presbycusis
Slower than sudden SNHL

 SNHL may fluctuate

 Vestibular symptoms in 50%, tinnitus in 25%-50%
 Otoscopy usually normal
 Diagnosis
 Appropriate review of systems
 CBC, ESR
 Immune Serology
RF, ANA, anti-dsDNA, anti-SSA/B, anti-
phospholipid Abs, C3+C4 levels, anti-gliadin

 Infectious Serology
FTA-ABS, HIV
 Role of anti-68 kD (HSP-70)
Western Blot (OTOblot)
 Detection of an Ab that binds to a 68-kD
purified recombinant inducible HSP-70 antigen
derived from bovine kidney cell line
 Predicting response to steroid therapy
 Presence of anti-HSP Abs on WB correlates with disease
activity and responsiveness to CS Tx (JAMA. 1994;24-
31;272(8):611-6)
 Role of anti-68 kD (HSP-70)
Western Blot (OTOblot)
 Based on the assumption that the 68 kDa protein
is the HSP-70
HSP 70 Abs are no more prevalent in AIED pts than in
controls. Thus, it is unlikely that the 68 kD protein is HSP 70
(Laryngoscope. 2003;113(10):1770-6)
HSP-70 may carry an epitope shared with the true target
antigen, or may otherwise colocalize with it biochemically

Western blot for an antibody to a 68-kD protein that binds

HSP-70 is not the standard of care in the evaluation of
AIED
 Additional Lab Tests
 Anti-myelin protein zero (P0) Abs
30 kD protein from guinea pig inner ear extracts
reported as target for Abs in sera from AIED patients.
However, a recent study concluded this Ab is not a
useful tool for diagnosis of AIED (Pham BN et al. Autoimmunity.
2007 May;40(3):202-7).

 Viral serology (EBV; HSV; VZV; CMV; RSV;

influenza A, B; parainfluenza 1–3; adenovirus
group; mumps)
Not recommended (García-Berrocal JR, ORL J Otorhinolaryngol
Relat Spec. 2008;70(1):16-19)
 Imaging
 MRI
 PET
Initial observed association between AIED
and a positive PET scan (Mazlumzadeh M et al. Otol
Neurotol. 2003 Mar;24(2):201-4)
Further research failed to show diagnostic
benefit (Matteson EL et al. Arthritis Rheum. 2005 Jun
15;53(3):337-42)
 Treatment

Gopen Q et al. Mechanisms underlying autoimmune inner ear disease, Drug Discov Today
2006;3(1) 137-142
 Corticosteroid therapy
 Mainstay of therapy
 High dose 4w therapeutic trial identifies
responders from nonresponders
15dB improvement in 1 freq.
10dB improvement in > 2 freq.
significant improvement in discrimination
 Corticosteroid therapy
 Tx duration
CS responders continue full-dose therapy until
monthly audiograms confirm a plateau of recovery,
with a slow tapering.
Maintenance dose – 10-20 mg
Tx < 6m associated with higher risk of relapse.

 ~ 60% Response rate

 Intratympanic CS
 Ineffective in guinea pig models
 Few clinical trials:
4/5 pts showed improvements in discrimination
but not SRT or pure tone (Silverstein H et al. Ear Nose Throat J
1996;75(8):468–471)
1/1 pts demonstrated improvement although
experienced several relapses (Parnes LS at al. Laryngoscope
1999;109(7 Pt 2):1–17)
5/8 pts with poor response to systemic CS
showed improved hearing (Garcia-Berrocal JR et al. Eur Arch
Otorhinolaryngol 2006;263(11):977–982)
 Immunomodulators
 Methotrexate
Early reports of possible efficacy
RCT: no more effective than placebo in
maintaining hearing improvement in steroid-
responsive AIED pts (Harris JP et al.. JAMA 2003;290(14):1875–
1883)

 Etanercept
Positive results as a tapering agent in CS
responsive pts
RCT: no better than placebo for treatment of CS
responsive AIED (Cohen S et al. Otol Neurotol 2005;26(5):903–907)
 Intratympanic Infliximab
Humanized TNF-α mab
Van Wijk F et al. 2006: transtympanic Infliximab
1/w for 4w
○ allowed steroid tapering in 4/5 steroid dependant
pts, improved hearing in 3/4 relapsed pts.
○ resulted in hearing improvement and reduced
disease relapse
 Azathioprine
Improvement shown in combination with Prednisone (Saraçaydin
)
A, J Int Med Res. 1993 Jul-Aug;21(4):192-6

Report of improved discrimination in 5/7 pts as 3rd line agent

(Lasak JM et al. Ear Nose Throat J 2001;80(11):808–811)

 IVIG
Report of stabilized hearing and subjective improvement in 1
patient refractory to Tx (Broughton SS at el, Semin Arthritis Rheum
2004;34(2):544–548)

 Mycophenolate mofetil
1 patient (Broughton SS at el, Semin Arthritis Rheum 2004;34(2):544–548)

 Plasmapheresis
8/16 pts showed improved long term hearing (Luetje CM, Berliner KI,
Am J Otol. 1997 Sep;18(5):572-6)
 Cyclophosphamide
Considered as last resort d/t high toxicity
McCabe (1979) reported improvement with
combined Tx of Cyclophosphamide and CS
Recent report of little benefit (Broughton SS et al.
Semin Arthritis Rheum 2004;34(2):544–548)
 Cochlear Implantation in
AIED
 Autoimmune disorders are associated with strial
vasculitis and formation of bone in the cochlea that
can impair the insertion of CI.
 Immunosuppressive therapy may impair wound
healing, reduce immune response and increase the
risk of complications (flap infection, extrusion of the
device, healing problems).
Quaranta N. 2002: implantation in 5 pts with AI disease was
successful, no complications occurred and excellent
postoperative speech perception was achieved (Acta Otolaryngol
Suppl. 2002;(548):44-8)

Vishwakarma R. 2007: Successful Implantation in a patient

with Cogan syndrome (Eur Arch Otorhinolaryngol. 2007 Oct;264(10):1121-4)
The End…