A

1. ORIGINAL ARTICLE
Relationship between disease activity and hearing impairment
in patients with rheumatoid arthritis compared with controls
Adem Yildirim1
& Gulseren Surucu1
& Sedat Dogan2
& Mehmet Karabiber1
Received: 30 September 2015 /Revised: 29 October 2015 /Accepted: 21 November 2015
# International League of Associations for Rheumatology (ILAR) 2015
Abstract The characteristics of hearing impairment (HI) in
rheumatoid arthritis (RA) are still poorly understood, and their
association with disease activity is based on conflicting infor-
mation. This study compared HI between RA patients and
controls and between active and remission RA groups using
multi-frequency audiometry. This study enrolled 88 RA pa-
tients and 50 controls. The pure-tone hearing thresholds at 500
to 4000 Hz for air (AC) and bone (BC) conduction were com-
pared between RA and controls as well as between active and
remission RA patients using DAS28-CRP scores. The pure-
tone hearing thresholds for AC and BC were significantly
higher at high frequencies (2000 and 4000 Hz) in the RA
group for both ears compared with controls. In addition, the
BC threshold at 1000 Hz for the right ear was higher in the RA
group than controls. When active and remission RA patients
were compared, the thresholds were higher only at 4000 Hz
for both ears for AC and BC in patients with active RA. The
air-bone gap differed significantly at 2000 and 4000 Hz in
both ears. This study demonstrated that patients with RA have
a heightened risk of HI, and disease activity increases this risk,
particularly at high frequencies. Clinicians who manage RA
should be aware of HI and consider performing audiological
evaluations in RA patients with active disease in particular.
Keywords Disease activity . Hearing impairment .
Rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disorder
that affects approximately 1 % of the population and is
characterised by inflammation of the synovial membranes of
diarthrodial joints, which leads to progressive destruction of
articular and periarticular tissues [1]. Extra-articular involve-
ment is a feature of RA and multiple organs and systems may
be affected. Although it is generally accepted that the auditory
system is negatively affected in patients with RA, the charac-
teristics of the hearing impairment (HI) are still poorly under-
stood. The HI in RA patients can be conductive, sensorineural,
or of mixed type. Many studies comparing patients with and
without RA found sensorineural HI in 25–72 % of patients,
conductive HI in 4–23 %, and some mixed-type HI [2–9].
Along with the primary erosive arthritis of the peripheral sy-
novial joints, the incudostapedial and incudomalleolar joints
of the middle ear may be affected, causing conductive HI.
However, extra-articular involvement (vasculitis and neuritis)
may also affect the cochlea and the cochlear nerve and lead to
sensorineural HI. The finding that sensorineural HI is more
frequent in RA patients and the fact that several parameters
(such as age, disease duration, drugs used, and disease activ-
ity) may affect HI have compelled researchers to investigate
more complex mechanisms.
Only a few studies have investigated the relationship be-
tween clinical or serological disease activity and HI, with var-
ious results [2, 5, 6, 9–12]. Disease activity was assessed using
various parameters, such as the erythrocyte sedimentation rate
(ESR) [2, 6, 9–11], C-reactive protein (CRP) [2, 11], rheuma-
toid nodules [6], rheumatoid factor (RF) [5, 10], bone erosions
The study was performed at the Education and Research Hospital of
Adiyaman University, Adiyaman, Turkey
* Adem Yildirim
ademyildirim@yahoo.com
1
Department of Physical Medicine and Rehabilitation, Medical
Faculty of Adiyaman University, Adiyaman, Turkey
2
Department of Otorhinolaryngology, Medical Faculty of Adiyaman
University, Adiyaman, Turkey
Clin Rheumatol
DOI 10.1007/s10067-015-3129-1

2. [5], the disease activity score-28 joints (DAS28) [11], and
anti-nuclear antibodies [5]. Some studies, but not others,
found a significant relationship between disease activity and
HI.
This study compared the HI in RAvs. controls as well as in
active vs. remission RA groups, which were determined using
the DAS28-CRP scores with multi-frequency audiometry. To
our knowledge, this is the first study investigating the effect of
disease activity using DAS28-CRP scores of HI in patients
with RA, in addition to comparing RA patients vs. controls
with a relatively large RA cohort.
Materials and methods
Setting and study population
This prospective controlled study was approved by the Ethics
Committee of Adiyaman University, Turkey. The study in-
cluded 88 RA patients with a minimum of 12 months of dis-
ease duration diagnosed according to the American College of
Rheumatology (ACR-1987) criteria and 50 rheumatic-
disease-free controls with normal audiometry tests. All partic-
ipants gave informed consent before joining the study. Pa-
tients with rheumatic disease other than RA, a perforated or
scarred tympanic membrane, otorrhoea, congenital HI, con-
genital head and neck anomalies, middle ear effusion, occu-
pational noise exposure, head trauma, chronic neurological
disease, Meniere’s syndrome, or ototoxic drug use (i.e.,
high-dose salicylate, streptomycin, etc.) were excluded from
the study.
Rheumatic evaluations
The same specialist physician performed the rheumatic eval-
uations of all 88 patients with RA. Disease duration, number
of tender and swollen joints, rheumatoid nodules, ESR, CRP,
and RF levels, radiographic findings, and history of drug use
were recorded. To monitor disease activity using a
standardised approach, composite indexes have been defined
based on the European League against Rheumatism (EULAR)
and ACR. These indices include parameters such as the num-
ber of tender and swollen joints, the patient’s pain measure-
ment, a global evaluation of disease activity by the patient and
physician, acute phase response, and functional assessment.
Among these composite indices, the DAS28 and its modifica-
tions, the DAS28-ESR, and DAS28-CRP are commonly used
to assess the disease activity and treatment response. In par-
ticular, the DAS28-CRP is a validated tool for assessing dis-
ease activity [13]; it is based on a count of 28 swollen and
tender joints and the CRP, with a score ranging from 0 to 9.4
(disease activity level: remission, <2.6; light, 2.6 to <3.2;
moderate, 3.2 to ≤5.1; high, 5.1 to <9.4). The disease activity
in all RA patients according to the DAS28-CRP was calculat-
ed and used as the basis for dividing patients into two groups:
the RARemission group, DAS28-CRP <2.6 and the RAActive
group, DAS28-CRP ≥2.6.
Audiometric evaluations
One experienced otologist conducted detailed otoscopic ex-
aminations of both ears in all participants. In a soundproof
room, an Interacoustics AC40 audiometric device for pure-
tone audiometry was used to obtain the absolute thresholds
for air (AC) and bone (BC) conduction at pure tone frequen-
cies of 500, 1000, 2000, and 4000 Hz. The air-bone gap
(ABG), which is the difference between the AC and BC
thresholds, was recorded. The audiometric and rheumatic
evaluations were performed concomitantly, and each special-
ist was blind to the other’s evaluation.
Statistical analysis
The Statistical Package for the Social Sciences ver. 18 (SPSS,
Chicago, IL, USA) was used for the statistical analyses. Ho-
mogeneity tests were performed to examine the normal distri-
butions of age and gender in the various groups. An indepen-
dent samples t test was used to compare the parametric values
of the RAvs. controls and the RARemission vs. RAActive groups.
A p value<0.05 was considered to indicate statistical
significance.
Results
Table 1 summarises the demographic data of the active and
remission RA patients and the controls. There were no signif-
icant differences between the RA and control groups with
respect to age (p=0.882) or gender (p=0.194) or between
the active and remission RA groups (p=0.470 for age, p=
0.130 for gender). The average disease duration of the RA
patients was 58±44 (12–192)months. Table 2 summarises
the disease characteristics: mean disease duration, number of
Table 1 Demographic data of subjects
Number of subjects Age (mean±SD) Gender
RARemission 26 48.3±12.5 10 M/16 F
RAActive 62 46.4±10.5 14 M/ 48 F
RAAll 88 46.9±11.1 24 M/64 F
Control group 50 46.7±7.9 19 M/31 F
All subjects 138 46.9±10.0 43 M/95 F
RA rheumatoid arthritis, M male, F female
Clin Rheumatol

3. tender and swollen joints, global activity score, and the ESR,
CRP, and DAS28 scores.
The AC and BC pure-tone hearing thresholds were signifi-
cantly higher at frequencies of 2000 and 4000 Hz in the RA
group than the controls for both ears. The BC thresholds at
1000 Hz for the right ear were also significantly higher in the
RA group relative to controls. The differences in the ABG were
not significant. Table 3 summarises the mean AC and BC
thresholds and ABG for both ears in the RA and control groups.
Comparing the active and remission RA patients, sig-
nificantly higher thresholds were found only at 4000 Hz
for the right and left ears for both AC and BC in pa-
tients with active RA. The thresholds at 500–2000 Hz
tended to be higher in the active RA group, but the
differences were not significant. The ABG differed sig-
nificantly at 2000 and 4000 Hz in both ears. Table 4
summarises the results for the RA patients according to
disease activity.
Discussion
Although several theories regarding HI in RA have been pro-
posed, the aetiopathogenesis of ear involvement is not fully
understood. Theories regarding the pathophysiology of HI
include inflammatory arthritis of the incudostapedial and
incudomalleolar joints leading to conductive HI [2, 6, 12],
auditory neuropathy induced by possible vasculitis, inflamma-
tion of the cranial nerve VIII [7, 14], inflammatory destruction
of the cochlear hair cells or inner ear with immune complex
deposition due to autoimmune processes [15], and the effects
of medicines used in RA (salicylates, nonsteroidal anti-
inflammatory drugs (NSAIDs), anti-malarial drugs, and
disease-modifying anti-rheumatic drugs) [16]. Sensorineural
HI seems to be more frequent in RA patients, based on extra-
articular involvement such as vasculitis and neuritis and re-
sults in hearing loss at higher frequencies [6]. We also found
significantly higher thresholds at high frequencies (2000 and
Table 2 Characteristics of RA
patients (mean±SD) RARemission (n=62) RAActive (n=26) RAAll (n=88)
Mean disease duration (months) 57.2±46.7 58.8±43.7 58.3±44.3
Number of tender joints 0.4±0.8 8.8±6.4 6.3±6.7
Number of swollen joints 0.0±0.0 3.7±3.2 2.6±3.2
Global activity score (mm) 27.3±13.1 51.3±23.3 44.2±23.5
Erythrocyte sedimentation rate (mm/h) 25.0±21.1 32.0±22.3 29.9±22.1
C-Reactive protein (mg/L) 5.5±5.4 15.1±21.8 12.3±19.0
DAS28-CRP 2.1±0.4 4.5±1.2 3.8±1.5
RA rheumatoid arthritis, DAS28-CRP disease activity score 28 joints C-reactive protein
Table 3 Analysis of audiogram (dB) by frequency of RA patients and controls (mean±SD)
Right ear Left ear
Frequency (Hz) RAAll (n=88) Controls (n=50) p RAAll (n=88) Controls (n=50) p
Air conduction 500 21.8±5.4 20.7±6.4 NS 21.1±6.7 19.1±4.9 NS
1000 19.6±5.0 18.0±4.2 NS 19.6±6.7 17.7±5.0 NS
2000 20.9±6.2 17.2±4.1 <.001 22.3±7.0 18.2±4.8 <.001
4000 28.0±6.0 20.8±4.2 <.001 27.6±7.1 20.3±6.1 <.001
Bone conduction 500 16.3±4.6 15.1±5.9 NS 16.1±5.5 14.9±3.4 NS
1000 15.5±5.3 13.4±2.8 <.05 15.2±6.4 14.2±4.2 NS
2000 15.7±5.9 13.0±3.4 <.01 16.8±6.2 13.9±3.4 <.01
4000 23.4±6.2 16.1±4.8 <.001 23.5±6.5 16.0±5.2 <.001
Air-bone gap 500 5.5±4.6 5.6±3.3 NS 4.9±4.6 4.2±4.1 NS
1000 4.1±3.3 4.6±4.3 NS 4.4±4.8 3.5±3.4 NS
2000 5.2±4.1 4.2±3.6 NS 5.6±3.3 4.3±4.3 NS
4000 4.6±2.9 4.7±2.3 NS 4.1±2.3 4.3±3.4 NS
Italic fonts indicate statistical significance
RA rheumatoid arthritis, NS not significant
Clin Rheumatol

4. 4000 Hz) in the RA group compared with the controls for both
ears and for both AC and BC. In addition, the BC thresholds at
1000 Hz for the right ear were also significantly higher in the
RA group. The differences in the ABG were not significant.
Similar to our results, Ozkiris et al. [17] found significant
differences in air conduction only at high frequencies (4000,
6000, and 8000 Hz) upon comparing RA patients with healthy
volunteers. They considered the hearing losses at high fre-
quencies to indicate cochlear involvement due to the systemic
vascular component of RA. However, they did not report the
BC or ABG differences. In a study of 36 RA patients and 36
healthy controls, Takatsu et al. [9] found that patients with RA
had significant hearing loss at 250, 500, 1000, and 2000 Hz
for AC and 2000 Hz for BC in both ears. They also found a
significant difference in ABG at 500 Hz (but not at other
frequencies) in both ears. They concluded that there was an
increased incidence of sensorineural HI in Japanese patients
with RA. By contrast, Murdin et al. [5] evaluated 55 relatively
young RA patients (<50 years old) and found significant HI in
RA patients, especially at low and intermediate frequencies,
but not at high frequencies, when compared with the norma-
tive population hearing threshold values according to age de-
cade and sex. They associated their results with endolymphat-
ic hydrops but did not provide a satisfactory pathophysiolog-
ical mechanism. Our results comparing RA vs. controls, find-
ing HI at the most high frequencies for both AC and BC,
suggest that the sensorineural HI results from extra-articular
involvement, such as vasculitis or neuritis affecting the co-
chlea and cochlear nerve, but do not support arthritic joint
involvement limited to the middle ear ossicular chain.
There is conflicting evidence regarding the association be-
tween disease activity and HI, and the reported data have been
inconsistent; some studies have reported correlations between
HI and disease activity, while others have failed to find any
association. When we compared the audiometric results of 62
patients with active disease based on the DAS28-CRP scores
(DAS28-CRP≥2.6) and 26 patients in remission (DAS28-
CRP<2.6), significantly higher thresholds were found only
at 4000 Hz in both ears for AC and BC in active RA patients.
Significant ABG differences were found at 2000 and 4000 Hz
in both ears. These results showed a relationship between
disease activity and HI and support the idea that patients with
active disease have further involvement, especially at high
frequencies. We think that the involvement at high frequencies
results from vasculitis and neuritis affecting the cochlea and
cochlear nerve, leading to sensorineural HI. In line with our
results, some authors have reported significant associations
between disease activity and HI. Magaro et al. [10] performed
audiometric evaluations in a relatively small RA cohort of 20
RA patients (13 active, 7 inactive RA) and found a positive
correlation between disease activity and HI. Similarly, in a
sample of 36 RA patients and 36 healthy controls, Takatsu
et al. [9] showed that the frequency of sensorineural HI is
related to the ESR and plasma interleukin-6 and matrix metal-
loproteinase-3. Dikici et al. [2] evaluated 20 RA patients and
20 healthy volunteers and concluded that higher ESR and
CRP levels were related to HI. Finally, in a recent study,
Pascual Ramos et al. [11] performed audiometric evaluations
in 113 RA patients who completed a 1-year follow-up using
ESR, CRP, and the DAS28-CRP to indicate disease activity.
Among the 80 patients without HI at baseline, 10 developed
incidental HI, and they had either more disease activity at
baseline or cumulative previous incidental HI. In addition,
the DAS28-CRP of these patients was significantly higher
Table 4 Analysis of audiogram
(dB) by frequency for RA patients
according to disease activity
(mean±SD)
Right ear Left ear
Frequency (Hz) RARemission RAActive p RARemission RAActive p
(n=62) (n=26) (n=62) (n=26)
Air conduction 500 20.4±4.2 22.3±5.8 NS 19.8±4.8 21.6±7.3 NS
1000 18.3±3.7 20.2±5.4 NS 18.5±5.1 20.1±7.2 NS
2000 19.6±3.4 21.5±7.0 NS 20.2±5.6 23.2±7.4 NS
4000 25.0±4.0 29.2±6.4 <.01 24.4±6.8 29±6.8 <.01
Bone conduction 500 15.6±3.6 16.5±4.9 NS 16.3±4.1 16.0±5.9 NS
1000 15.0±4.0 15.6±5.8 NS 14.0±4.0 15.6±7.1 NS
2000 16.2±3.6 15.6±6.7 NS 16.0±4.9 17.1±6.6 NS
4000 21.3±3.9 24.2±6.8 <.05 21.2±5.7 24.4±6.6 <.05
Air-bone gap 500 4.8±4.4 5.8±4.6 NS 3.5±4.2 5.6±4.7 NS
1000 3.3±3.1 4.5±3.4 NS 4.4±5.4 4.4±4.6 NS
2000 3.5±2.7 5.9±4.4 <.05 4.2±3.9 6.1±2.8 <.05
4000 3.7±2.3 5.0±3.0 <.05 3.3±3.1 4.5±1.7 <.05
Italic fonts indicate statistical significance
RA, rheumatoid arthritis; NS, not significant
Clin Rheumatol

5. than that of the remaining 70 patients. The authors stated that
the cumulative disease activity evaluated with the DAS28-
CRP was the only predictor of incidental HI.
By contrast, Ozcan et al. [6] evaluated 37 RA patients and
35 healthy volunteers and failed to find an association be-
tween audiometric evaluations and disease activity. They used
ESR levels and rheumatoid nodules as criteria of disease ac-
tivity. We believe that an assessment of disease activity using
only these two parameters is insufficient. Similarly, Murdin et
al. [5] found no associations between disease characteristics
(DAS28, anti-nuclear antibody status, RF status, presence of
nodules and bony erosions, disease duration, anti-rheumatic
drug therapy) and hearing thresholds in 55 RA patients. They
compared the auditory data of the RA patients with the normal
population hearing threshold values, but did not compare ac-
tive RA patients and patients in remission. Finally, Salvinelli
et al. [12] studied 38 RA patients (20 active, 18 inactive RA)
and 38 healthy volunteers, but failed to find impairment in
hearing thresholds between active and inactive RA patients,
although they observed marked differences between RA pa-
tients and controls. Their disease activity parameters (sedi-
mentation ≥50 mm/h, RF positivity, tender joints ≥6, swollen
joints ≥3, morning stiffness ≥30 min) correspond to high dis-
ease activity levels according to DAS28-CRP scoring. How-
ever, if patients with medium or low disease activity had been
included, it may have been possible to identify a significant
association between disease activity and HI.
Although a few studies found no association between dis-
ease activity and HI, we think that this arises from the methods
used to measure disease activity. Currently, clinicians use the
DAS28-CRP to assess disease activity based on a count of 28
swollen and tender joints, in addition to a measure of the pa-
tient’s global activity score and CRP level. We also believe that
the DAS28-CRP is a more accurate measure of disease activity.
The main limitation of our study is its cross-sectional de-
sign; we could not compare our data with follow-up results
after recovery. Although we excluded patients using ototoxic
drugs (i.e., high-dose salicylate, streptomycin, etc.), we did
not discuss the possible effects of anti-rheumatic drug
use in the RA cohort (e.g., methotrexate, chloroquine,
sulfasalazine, etc.). Nevertheless, a large prospective
study by Kastanioudakis et al. [18] found no correlation
between drug intake (NSAIDs except salicylates,
hydroxychloroquine, D-penicillamine, and methotrexate)
and sensorineural HI.
In conclusion, this is the first study to investigate the effects
of disease activity using DAS28-CRP scores on HI in patients
with RA, as well as to compare RA patients vs. controls with a
relatively large RA cohort. We found that patients with RA
have a higher risk of HI and that disease activity increases this
risk, especially at high frequencies. Clinicians who are inter-
ested in the treatment and management of RA should be aware
of HI, especially in patients with active disease. Therefore, we
recommend performing annual audiological evaluations and
taking necessary precautions.
ABG air-bone gap, AC air conduction, BC bone conduc-
tion, CRP C-reactive protein, DAS28-CRP disease activity
score 28 joints-C-reactive protein, ESR erythrocyte sedimen-
tation rate, HI hearing impairment, RA rheumatoid arthritis,
RF rheumatoid factor,
Compliance with ethical standards
Disclosures None.
Ethical approval This study was approved by the Ethics Committee of
Adiyaman University, Turkey. All participants gave informed consent
before joining the study.
References
1. Elwany S, el Garf A, Kamel T (1986) Hearing and middle ear
function in rheumatoid arthritis. J Rheumatol 13(5):878–881
2. Dikici O, Muluk NB, Tosun AK, Unlusoy I (2009) Subjective
audiological tests and transient evoked otoacoustic emissions in
patients with rheumatoid arthritis: analysis of the factors affecting
hearing levels. Eur Arch Otorhinolaryngol 66(11):1719–1726
3. Lutf A, Poil AR, Hammoudeh M (2014) Characteristics of patients
with rheumatoid arthritis in Qatar: a cross-sectional study. Int J
Rheum Dis 17(1):63–65
4. Milisavljevic D, Stankovic M, Zivic M, Radovanovic Z, Stankovic
P (2010) Changes in auditory ossicles in rheumatoid arthritis: scan-
ning electron microscopic study. Eur Arch Otorhinolaryngol
267(3):363–366
5. Murdin L, Patel S, Walmsley J, Yeoh LH (2008) Hearing difficul-
ties are common in patients with rheumatoid arthritis. Clin
Rheumatol 27(5):637–640
6. Ozcan M, Karakus MF, Gunduz OH, Tuncel U, Sahin H (2002)
Hearing loss and middle ear involvement in rheumatoid arthritis.
Rheumatol Int 22(1):16–19
7. Ozturk A, Yalcin S, Kaygusuz I, Sahin S, Gok U, Karlidag T et al
(2004) High-frequency hearing loss and middle ear involvement in
rheumatoid arthritis. Am J Otolaryngol 25(6):411–417
8. Raut VV, Cullen J, Cathers G (2001) Hearing loss in rheumatoid
arthritis. J Otolaryngol 30(5):289–294
9. Takatsu M, Higaki M, Kinoshita H, Mizushima Y, Koizuka I (2005)
Ear involvement in patients with rheumatoid arthritis. Otol
Neurotol 26(4):755–761
10. Magaro M, Zoli A, Altomonte L, Mirone L, Corvino G, Di
Girolamo S et al (1990) Sensorineural hearing loss in rheumatoid
arthritis. Clin Exp Rheumatol 8(5):487–490
11. Pascual-Ramos V, Contreras-Yanez I, Rivera-Hoyos P, Enriquez L,
Ramirez-Anguiano J (2014) Cumulative disease activity predicts
incidental hearing impairment in patients with rheumatoid arthritis
(RA). Clin Rheumatol 33(3):315–321
12. Salvinelli F, Cancilleri F, Casale M, Luccarelli V, Di Peco V,
D'Ascanio L et al (2004) Hearing thresholds in patients affected
by rheumatoid arthritis. Clin Otolaryngol Allied Sci 29(1):75–79
13. Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de
Putte LB, van Riel PL (1995) Modified disease activity scores that
include twenty-eight-joint counts. Development and validation in a
Clin Rheumatol

6. prospective longitudinal study of patients with rheumatoid arthritis.
Arthritis Rheum 38(1):44–48
14. Kakani RS, Mehra YN, Deodhar SD, Mann SB, Mehta S (1990)
Audiovestibular functions in rheumatoid arthritis. J Otolaryngol
19(2):100–102
15. Barna BP, Hughes GB (1988) Autoimmunity and otologic disease:
clinical and experimental aspects. Clin Lab Med 8(2):385–398
16. Jung TT, Rhee CK, Lee CS, Park YS, Choi DC (1993) Ototoxicity
of salicylate, nonsteroidal antiinflammatory drugs, and quinine.
Otolaryngol Clin N Am 26(5):791–810
17. Ozkiris M, Kapusuz Z, Gunaydin I, Kubilay U, Pirti I, Saydam L
(2014) Does rheumatoid arthritis have an effect on audiovestibular
tests? Eur Arch Otorhinolaryngol 271(6):1383–1387
18. Kastanioudakis I, Skevas A, Danielidis V, Tsiakou E, Drosos AA,
Moustopoulos MH (1995) Inner ear involvement in rheumatoid
arthritis: a prospective clinical study. J Laryngol Otol 109(8):713–
718
Clin Rheumatol