The use of teprotumumab in the treatment of TED has been transformative, with 5,845 patients completing 8 infusions as of July 2022[3]. The increasing use of teprotumumab has corresponded with a growing body of data citing potential adverse events[16].
In phase 2 and 3 RCTs, 10% of patients reported otologic symptoms1,2. All of these patients completed treatment and all of them resolved except one patient with a history of noise induced tinnitus[1],[2],[17]. In our study, 5 out of 52 (10%) patients had decreased hearing and 4 /5 of these patients could be identified based on previous history. This rate is based on gold standard pre and post treatment audiometry assessment.
Unlike other studies, this rate reflects an unbiased assessment and includes audiology assessment throughout treatment. Earlier studies have suggested a much higher incidence. In one case series of 28 patients, 4 were found to have hearing loss (14%). This was a retrospective study so none of the patients had baseline audiometry available for comparison. A later study of 27 patients found that 6 (22%) patients had unresolved hearing loss. Only 6 of the 27 patients had baseline audiometry which indicated that 5/6 (83%) of this group had hearing dysfunction before treatment[9]. Further, in the latter series, patients had an average of 7 out of 8 infusions,
In our analysis, patients with normal baseline audiometry, hearing loss was rare, with only 1 /32 patients being affected at 6 months follow up. This patient remained asymptomatic from baseline, through treatment, to 6 months follow up. Overall, in this group, there was a mean decrease of 0.78 dBHLs following treatment (95% CI: -1.3 to -0.3). To put this in context, the sound of normal breathing is as loud as 10 dBHLs[18].
Further, in our study, over one-third of patients had hearing dysfunction on audiometry at baseline. This group was significantly older and had a higher CAS than the population that had normal hearing at baseline. In the US, the prevalence of hearing related issues in this age group ranges from 19 to 29% (19% prevalence in ages 45 to 64 and 29% for those aged over 65)[19].The increased incidence of hearing dysfunction in TED patients at baseline might be explained by the potential impact of autoimmune thyroid disease and/or its treatment on hearing. Hearing impairment has been associated with thyroid abnormalities and autoimmunity in previous studies[20],[21]. In Graves’ disease, studies have suggested a decrease in hearing ability especially at high frequencies; particularly, pure tone audiometric testing showed mild to moderate sensorineural hearing loss (SNHL) in 23.5% of Graves’ disease patients[21]. Hearing impairment has also been associated with antithyroid medications, namely propylthiouracil, although rare[22],[23].
Of those with an abnormal audiogram at baseline, 10 /20 had hearing loss at 24 weeks, with 6 /10 (60%) improving by the 6 months follow up visit. Four of the 10 patients (40%) did not improve. Three of the patients from this group had severe hearing loss due to a stroke, occupational hearing loss and presbycusis prior to therapy with teprotumumab.
Overall Incidence and Predictors of Hearing Loss
In this study, one patient (2%) had new onset hearing loss, while 4 / 52 (8%) of patients had baseline hearing loss that worsened following treatment. Hearing loss in this group of patients did not improve after 6 months. Our results support the findings of Kossler and colleagues who observed that baseline hearing loss was a significant risk factor for further hearing loss following teprotumumab therapy[9].
Otologic Symptoms
In the present study, 29% reported subjectively of new otologic symptoms, this differs from the findings of the phase 2 and 3 RCTs with teprotumumab where only 10% spontaneously reported hearing related symptoms with 5% of these judged to be related to the drug [1],[2]. Further, like the RCTs, the majority (11 / 15) had complete resolution of their symptoms. These findings reinforce the importance of quantifiable baseline audiometry to monitor changes in hearing related to therapy.
Potential Relationship between the IGF-1R Pathway and Hearing Dysfunction
Teprotumumab is an insulin-like growth factor-1 receptor (IGF-1R) inhibitor which binds to IGF-1R and blocks its activation and signaling[24]. The Insulin-like growth factor-1 (IGF-1) and its high affinity receptor, IGF-1R, are expressed in the developing inner ear where they maintain cell survival and proliferation.[25],[26],[27] Animal studies suggest a role for IGF-1 in the development and protection of hearing function within the inner ear, which is supported by human studies.[26][28][29][30] IGF-1 maintains and prevents apoptosis of hair cells via downstream signaling pathways in the cochlea.[31] It is thought to promote the regeneration of cochlear ribbon synapsis, and it is also involved in the synaptic neurotransmission of the cochlear nuclei.[31] Definitive causal relationships have not been found between IGF-1R inhibition and hearing changes.
Limitations
Our study was limited by a follow up of 6 months. We noted a gradual improvement in the audiometry and symptoms of those with hearing loss / ontological symptoms with time. It is possible that with longer follow up, the prevalence of these signs and symptoms may have reduced.
Recommendations for Audiology Screening
In our study, 37% of patients had hearing dysfunction prior to therapy. This is significantly higher than expected for the average age of this group. Our results are supported by previous studies that also found a greater risk of hearing dysfunction associated with autoimmune thyroid disease and its treatment[20],[22]. Our study also found that hearing loss at baseline was a significant risk factor for deterioration in hearing following treatment with teprotumumab. Based on these findings, we set forth recommendations for screening prior to therapy and management following detection of abnormalities.
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All patients should have in office, baseline pure tone audiometry (air conduction) at the following frequencies: 0.25, 0.5, 1, 2, 4 and 8 kHz before treatment.
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If hearing dysfunction is found, these patients should be counselled on the increased risk of further hearing loss based on their current level of hearing.
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Physicians may consider reduction in exposure by reducing the dose of teprotumumab for those patients with pre-existing hearing loss. Although there are no study data on this reducing the risk other than a case report[32], it is a reasonable clinical option as most ototoxic drug induced events are related to drug exposure. In our office, we halve the dose of treatment at each visit, or one could consider increasing the duration between treatments, so that patients have 1 treatment every 6 weeks.
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Audiometry should be conducted at each visit prior to their infusion. If hearing loss is found (> 20 dB pure-tone threshold shift at one frequency and / or a > 10 dB shift at each of 2 consecutive frequencies, or threshold response shifting to “no response” at 3 consecutive test frequencies),[12] the patient should be referred to an audiologist for further assessment.