Hearing Loss in the Sjogren Syndrome

Bruno Tumiati, MD; Patrizia Casoli, MD; and Alfredo Parmeggiani, MD Background: Ear involvement is not unusual in autoimmune diseases, but few data on this problem in the Sjogren syndrome are available. Objectives: To determine whether the incidence of hearing loss is increased in patients with the Sjogren syndrome and to determine what factors might be involved in the pathogenesis of Sjogren syndrome-related hearing loss. Design: Cross-sectional study. Setting: Secondary referral center in Italy. Patients: 30 women with the Sjogren syndrome were evaluated for evidence of audiovestibular disorder. Their results were compared with those of 40 age-matched healthy women. Measurements: Evaluation techniques included pure tone audiometry thresholds at octave frequencies of 125 Hz to 8000 Hz, tympanometry, and the stapedial reflex test in both ears. The presence of vasculitis, the Raynaud phenomenon, nervous system involvement, and serum anticardiolipin antibodies was recorded. Results: 14 patients with the Sjogren syndrome (46% [95% CI, 28% to 66%]) had sensorineural hearing loss. Only one control (2.5% [CI, 0.06% to 13%]) had a similar hearing impairment (P< 0.001). Nine of the 14 patients who had the Sjogren syndrome and sensorineural hearing loss (64% [CI, 36% to 87%]) had anticardiolipin antibodies compared with only 3 controls (18% [CI, 4% to 45%]) (P = 0.02). Conclusion: The high prevalence of hearing loss in the Sjogren syndrome supports the value of doing audiometric studies before excluding cranial nerve involvement in this disease. The correlation of sensorineural hearing loss with anticardiolipin antibodies must be investigated further.

ar involvement in autoimmune diseases is not unusual. Sensorineural hearing loss is commonly reported as the first otologic manifestation of Wegener granulomatosis (1), polyarteritis nodosa (2), systemic lupus erythematosus (3), and rheumatoid arthritis (4, 5). Furthermore, although a high prevalence of cranial neuropathies resulting from the Sjogren syndrome is generally recognized, symptoms and signs of eighth-nerve disorder have not been specifically sought (6). The lack of published data on the connection between the Sjogren syndrome and auditory function prompted us to study whether such a relation exists and, if it does, to determine its pathogenesis.
Methods Patients

The initial study sample consisted of 31 women with a mean age of 52 years. These were all of the patients with the Sjogren syndrome who were consecutively seen at Reggio Emilia Hospital (a secondary referral center) in Reggio Emilia, Italy, from April 1993 to May 1995. Patients were classified as having primary Sjogren syndrome by the criteria established by Vitali and colleagues (7). All patients had objective keratoconjunctivitis sicca, xerostomia, and biopsy specimens from the minor salivary gland that were class 3 or higher (8). No patient met the criteria for any other connective tissue disease. Forty-five female blood donors volunteered to serve as controls and were matched with the patients for age. No control had a history of or symptoms compatible with such autoimmune diseases as xerophthalmia, xerostomia, or the Raynaud phenomenon. Inclusion criteria for both groups were intact tympanic membranes without visible scarring; no previous use of ototoxic drugs; and no history of otorrhea, otologic surgery, exposure to occupational or recreational noise, and skull trauma or infection of the upper respiratory tract at least 1 month before the study began. Thirty patients with the Sjogren syndrome and 40 controls met these criteria. All patients gave written informed consent.
Audiologic Evaluation

Ann Intern Med. 1997;126:450-453. From Ospedale Santa Maria Nuova, Reggio Emilia, Italy. For current author addresses, see end of text.

Otologic evaluation, including pneumatic examination with a hand-held micro-otoscope, was done by the same otolaryngologist in all patients.

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Audiologic tests, including the assessment of pure tone air and bone conduction thresholds, were conducted in a soundproof chamber with an Amplaid 455 audiometer (Ampliphon, Milan, Italy), calibrated according to the criteria of the American National Standards Institute. Pure tone thresholds at 125, 250, 500, 1000, 2000, 4000, and 8000 Hz were calculated for each ear. Hearing was classified as subnormal if the patient's audiogram was more than 20 dB below the accepted normal reading for the patient's age group at more than one test frequency in one or both ears. Patients with sensorineural hearing loss were further assessed by use of such supraliminal tests as the Fowler balance test, the Short Increment Sensitivity Index, and the Rosemberg threshold tone decay test. As measured by the tone decay test, decay greater than 15 dB within 1 minute was considered pathologic. Scores on speech reception threshold and speech discrimination tests were then evaluated. Middle-ear pressure was measured, and tympanometric graphs were plotted by using a Grason-Stadler GS33/1 acoustic impedance meter (Grason-Stadler, Inc., Littleton, Massachusetts) at a probe tone frequency of 220 Hz; Jerger and Jerger's differentiation of tympanograms (9) was used to analyze the study data. The ipsilateral and contralateral stapedius reflexes were tested using pure tones (500 to 4000 Hz). Patients with bilateral, symmetrical sensorineural hearing loss and cochlear involvement did not have further testing. Patients with unilateral deafness and supraliminal test results that suggested retrocochlear disease were evaluated for brainstem auditory evoked potentials; a positive result on this test was followed by magnetic resonance imaging.
Immunologic Evaluation

Table 1 .

Clinical and Laboratory Variables in Patients w i t h t h e Sjogren Syndrome

Variable

Patients with Sensorineural Hearing Loss in = 14) 55 14 2-10 8 6 14 14 12 9 3 7 3

Patients without Sensorineural Hearing Loss (n=16) 52 12 2-9 9 7 16 13 7 3 4 5 4

Mean age SD, y Range of duration of disease, y Erythrocyte sedimentation rate, n < 6 0 mm/h > 6 0 mm/h Antinuclear antibody titer > 1 : 3 2 0 , n Presence of antibodies to Ro (SS-A), n Presence of antibodies to La (SS-B), n Presence of anticardiolipin antibodies, n* Peripheral neuropathy, n Raynaud phenomenon, n Vasculitis, n * P = 0.02.

We tested patients for autoantibodies, including antinuclear antibodies, by using kidney and Hep-2 substrate. The presence of antibodies to Ro (SS-A), antibodies to La (SS-B), and IgG and IgM anticardiolipin antibodies was determined by using enzyme-linked immunosorbent assay (10). Rheumatoid factor was detected in serum samples by using a rheumatoid arthritis latex test.
Statistical Analysis

marized in Table 1. Antinuclear antibodies at a titer of 1:320 or greater were present in all 30 patients. Twenty-seven of 30 patients had antibodies to Ro, and 20 of 30 had antibodies to La. Results of rheumatoid factor testing were positive in 28 of 30 patients. Three patients had a history of skin lesions for which biopsy had been done; leukocytoclastic vasculitis had subsequently been diagnosed in these patients. Biopsy was done in 4 patients who presented with palpable purpura, and the presence of vasculitis was confirmed. The results of audiologic assessment showed that patients with the Sjogren syndrome had a higher prevalence of sensorineural hearing impairment than did their normal counterparts (Table 2). Fourteen of the 30 patients with the syndrome had sensorineural hearing loss (46% [95% CI, 28% to 66%]); this condition was bilateral in 10 patients and unilateral in 4 patients. Nine of 14 patients were asymptomatic and had hearing loss that was detectable only on audiologic testing. Hearing loss in the remaining 5 patients was clinically significant: Four patients had moderate hearing loss (35 to 54
Table 2. Incidence of Hearing Loss in Patients w i t h t h e Sjogren Syndrome and in Controls

Variable

Statistical analyses were done by using SAS software, version 6.0 (SAS Institute, Cary, North Carolina). The Fisher exact test was used to compare percentages, and 95% CIs were calculated. All P values were two tailed; a P value less than 0.05 was considered statistically significant.
Results

Persons with Unilateral Hearing Loss n

Persons with Bilateral Hearing Loss

Total Persons

n (%)

The demographic and clinical data of the 30 study patients with the Sjogren syndrome are sum-

Patients with the Sjogren syndrome in = 30) Sensorineural hearing loss Conductive hearing loss Controls (n = 40) Sensorineural hearing loss Conductive hearing loss * P< 0.001.

4 0 0 0

10 1 1 1

14(46)* 1(3) 1 (2.5) 1 (2.5)

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dB) and 1 had severe hearing loss (55 to 74 dB), classified on the basis of average pure tone score for speech frequencies of 500, 1000, and 2000 Hz. In contrast, only one control (2.5% [CI, 0.06% to 13%]) had sensorineural hearing loss (P < 0.001). One patient with the Sjogren syndrome and one control showed mild bilateral conductive hearing loss. The audiometric configuration for 12 patients with the Sjogren syndrome who had sensorineural hearing loss sloped at a high frequency (2000 to 8000 Hz); the configuration for the remaining 2 patients was essentially flat. The one control with sensorineural hearing loss had a flat audiometric configuration. In two patients with serious unilateral deafness, results of supraliminal tests and speech audiometry showed discrimination scores consistent with retrocochlear disease. We therefore did brainstem auditory evoked potentials and cerebral magnetic resonance imaging. The results of these tests were negative for pontocerebellar diseases. Middle-ear pressure was normal in all patients and all controls. No significant differences in mean compliance value were found between the patients with the Sjogren syndrome and the controls. In the Sjogren syndrome group, no significant statistical relation was found between sensorineural hearing loss and patient age, erythrocyte sedimentation rate, or previous treatment with steroids. The Raynaud phenomenon was present in seven patients with sensorineural hearing loss (50%) and five normoacusic patients (31%); this difference was not statistically significant. No relation between impaired hearing acuity and the presence of vasculitis was seen: Vasculitis was mainly restricted to the skin and was present in three patients with sensorineural hearing loss and four normoacusic patients with the Sjogren syndrome. No statistically significant difference was found in disease duration between patients with abnormal hearing and those with normal hearing. Furthermore, no correlation was found between hearing loss and antinuclear antibody and C3 and C4 levels. Nine of the 14 patients with the Sjogren syndrome who had sensorineural hearing loss (64% [CI, 36% to 86%]) had anticardiolipin antibodies compared with 3 patients (18% [CI, 4% to 45%]) in the normal hearing group (P = 0.02). Of these 9 patients, 3 were positive for IgG anticardiolipin antibodies, 2 were positive for IgM antibodies, and 4 were positive for IgG and IgM antibodies. Two patients with hearing loss and 1 patient without hearing loss had a false-positive result on the VDRL test. Of the 30 patients with the Sjogren syndrome, 90% had antibodies to Ro and 66% had antibodies to La. Antibodies to Ro were present in
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all patients with the Sjogren syndrome who had sensorineural hearing loss.
Discussion

Our results accord with those of previous investigators who showed a high prevalence of sensorineural hearing loss in patients with autoimmune diseases. Involvement of the middle ear is commonly described in patients with Wegener granulomatosis, with an incidence of 35% to 47% (1). Some studies of patients with rheumatoid arthritis have shown a prevalence of inner-ear disease ranging from 26% to 48%. This incidence does not correlate with age; sex; duration of disease; or previous therapy with salicylates, steroids, or other drugs (4, 5). In a controlled study of patients with systemic lupus erythematosus (3), 57% of patients had sensorineural hearing loss that was not correlated with the severity of the underlying disease or the presence of vasculitis. A high prevalence of cranial neuropathies is an accepted consequence of the Sjogren syndrome. In addition, symptoms and signs of eighth-nerve disorder have been reported in some cases (6). It appears, however, that most physicians who regularly treat patients with the Sjogren syndrome do not routinely ask them about hearing or balance or test them for audiologically detectable hearing loss. This suggests that the association between the Sjogren syndrome and sensorineural hearing loss was not previously made because it had not been actively sought. In 1971, Doig and colleagues (11) reported six cases of hearing loss in 22 patients with the Sjogren syndrome that was not complicated by connective tissue disorder. Only 1 patient in Doig and colleagues' study presented with sensorineural hearing loss; conductive hearing loss was found in the other patients on audiologic testing. However, this study did not include a healthy control group and was done before clear criteria for the diagnosis of the Sjogren syndrome were established. The results of our audiologic assessment showed that persons with the Sjogren syndrome had a higher prevalence of sensorineural hearing loss than did their normal counterparts. We found no relation between hearing loss and the duration and severity of the Sjogren syndrome, the presence of other extraglandular complications, or previous corticosteroid therapy. The Raynaud phenomenon was present in a substantial but not statistically significant proportion of the patients with sensorineural hearing loss. A higher prevalence of anticardiolipin antibodies was seen in patients with the Sjogren syndrome who had associated sen-

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sorineural hearing loss. In other studies (12-14), the frequency with which anticardiolipin antibodies have been detected in cases of primary Sjogren syndrome has ranged from 6% to 52%. In our study, 12 patients (40%) were positive for anticardiolipin antibodies; 9 of these patients had sensorineural hearing loss. This suggests the possibility of a biological association between anticardiolipin antibodies and sensorineural hearing loss (P = 0.02) (Table 1). The pathogenesis of immune-mediated sensorineural deafness is unclear, but it may include immunocomplex-mediated vasculitis in the inner ear (15) or autoantibodies directed against inner-ear antigenic epitopes (16). Two recent case reports (17, 18) suggest that anticardiolipin antibodies may be associated with sudden sensorineural hearing loss in patients with autoimmune diseases. Moreover, falsepositive results on tests for syphilis have been seen in 8% of patients with the Cogan syndrome, a disease characterized by audiovestibular symptoms; nonsyphilitic interstitial keratitis; and, frequently, systemic features (19). Our results are also consistent with the possibility that anticardiolipin antibodies are responsible for sensorineural hearing loss in the Sjogren syndrome; however, previous data have not uniformly shown a relation between anticardiolipin antibodies and nervous system complications in this disease (20). In conclusion, the high prevalence of hearing loss in the major autoimmune diseases, including systemic lupus erythematosus; rheumatoid arthritis; and, now, the Sjogren syndrome, suggests the need to do audiometric studies in patients with this syndrome before the involvement of cranial nerves is excluded. More extensive studies of anticardiolipin antibodies in patients with sensorineural hearing loss of unknown origin or hearing loss associated with autoimmune diseases are needed to exclude or confirm the role of these autoantibodies in the pathology of the inner ear.
Acknowledgment: The authors thank Mrs. Antonella Berselli for technical assistance. Requests for Reprints: Bruno Tumiati, MD, 2nd Department of Internal Medicine, Ospedale S. Maria Nuova, Viale Risorgimento, 42100 Reggio Emilia, Italy.

Current Author Addresses: Drs. Tumiati and Casoli: 2nd Department of Internal Medicine, Ospedale S. Maria Nuova, Viale Risorgimento, 42100 Reggio Emilia, Italy. Dr. Parmeggiani: Department of Otolaryngology, Ospedale S. Maria Nuova, Viale Risorgimento, 42100 Reggio Emilia, Italy.

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