The Impact of Monoclonal Antibody Usage on Hearing Outcomes: A Systematic Review.

INTRODUCTION

Monoclonal antibodies are laboratory manufactured clones of antibody proteins with high specificity for a specific antigen. While initially utilized predominantly in organ transplantation, rheumatoid arthritis, and hematologic cancers, recent years have seen expansion to new fields, including thyroid eye disease, Alzheimer's disease, and chronic migraine. 1 Technological advancements and the expansion of antibody targets to treat a vast breadth of disease underlies the rise of these agents' more widespread use. 2 Conditions targeted by monoclonal antibodies have grown to encompass oncologic and inflammatory‐based diseases, neurologic pathologies, and transplantation. As these agents gain more popularity, it is critical to understand both short‐ and long‐term implications associated with their adverse effects, which can have substantial effects on patients' quality of life.

Unforeseen reactions from monoclonal antibodies can range from transfusion reactions to hypersensitivity reactions, as well as organ‐specific adverse effects. 3 Monoclonal antibodies have been reported to have impact on hearing function, which are postulated to be a result of intracochlear mechanisms such as drug‐induced vasculitis of the inner ear arteries or cross‐reactivity resulting in impaired hair cell function. 4 , 5 Symptoms of toxicity to the auditory and vestibular organs include hearing loss, tinnitus, aural fullness, vertigo, and dizziness, which have been commonly reported with a variety of drug classes including, but not limited to, platinum‐based chemotherapeutic agents, aminoglycoside antibiotics, and loop diuretics. 6

As this rapidly expanding class of agents continues to grow, otolaryngologists may increasingly be called upon to evaluate patients with otologic symptoms in the setting of therapy with monoclonal antibodies. In this systematic review, we synthesize reports of monoclonal antibody usage resulting in reported effects on hearing function. Where available, audiometric data from studies are presented to further characterize these effects, as well as proposed mechanisms of ototoxicity.

METHODS

This study was exempt from approval by the University of Pennsylvania Institutional Review Board. A systematic review was performed in accordance with standardized PRISMA guidelines. 7

Search Strategy and Study Selection

The authors sought to assess the ways in which patients treated with monoclonal antibodies experienced otologic effects through the following PEO question: In adult patients undergoing treatment with immunomodulatory monoclonal antibodies, what agents are implicated in ototoxic adverse effects and what proportion of patients experience these effects? It was hypothesized that effects toxic in nature to hearing outcomes following the usage of monoclonal antibodies would be identified. A systematic literature search was performed in PubMed, Embase, and Scopus on June 22, 2024. Search strings were formatted to identify publications reporting a relationship between the usage of a monoclonal antibody and hearing loss. The search string was formatted as follows: (“monoclonal antibody”:ab,ti OR “monoclonal antibodies”:ab,ti OR “immune checkpoint inhibitors”:ab,ti OR “checkpoint”:ab,ti OR “nivolumab”:ab,ti OR “ipilimumab”:ab,ti OR “pembrolizumab”:ab,ti OR “teprotumumab”:ab,ti OR “muronomab”:ab,ti OR “rituximab”:ab,ti OR “infliximab”:ab,ti OR “dupilumab”:ab,ti) AND (“hearing loss”:ab,ti OR “sudden hearing loss”:ab,ti OR “sensorineural hearing loss”:ab,ti). There were no temporal limits applied to the search. Articles were managed using Covidence systematic review software (Veritas Health Innovation, Australia, 2020).

A total of 1084 studies were retrieved from database search. Following removal of duplicates, 757 article were imported for screening. Study types included clinical case reports and series, prospective studies, and retrospective studies. Articles were eligible for inclusion if they reported upon hearing loss occurring with monoclonal antibody use in adult patients. Reporting of audiometric data was not required to be included for review. Pediatric patients were excluded given different age‐based audiometric criteria and techniques for hearing assessment in this population. Exclusion criteria encompassed articles where an immunomodulatory agent or antibody was not mentioned, hearing loss was not mentioned, conference abstracts, non‐English articles, review articles, animal models, and articles reporting only pediatric data or where adult and pediatric data could not be isolated. Two authors (P.A. and Y.S.) performed the initial review of the literature and a third (A.E.Q.) served as an adjudicator. Full‐text articles were reviewed by the same two authors (P.A. and Y.S.) and adjudicated by a third (A.E.Q). Reference lists of included full‐text articles were additionally reviewed to identify articles for inclusion. A PRISMA flow diagram is indicated in Figure 1 . 8

Data Collection

Data recorded from each article included baseline study characteristics, including title, authorship, country of origin, publication year, publication journal, study design, and sample size. In subjects with ototoxicity attributed to monoclonal antibody usage, information recorded included age, gender, monoclonal antibody studied, indication(s) for monoclonal agent use, length of treatment, follow‐up timeline, concurrent medications, comorbidities, pre‐ and posttreatment audiometric data at low, middle, high, and ultrahigh frequencies when available, pattern of audiometric data (SNHL vs. CHL, laterality, severity), tympanometry, word recognition score (WRS), speech recognition threshold (SRT), treatment for ototoxicity (if observed), and reversal (if observed) with audiometric data (if provided). Frequency ranges were defined as follows: low (250–500 kHz), middle (1–3 kHz), high (4–8 kHz), ultrahigh (>8 kHz). Medication‐induced ototoxicity was determined usually by established guidelines from the American Speech‐Language‐Hearing Association (ASHA): 20 dB threshold decrease at any frequency, 10 dB decrease at any two consecutive frequencies, or no response at three consecutive frequencies when responses were previously present. 9

Data Analysis

A quantitative synthesis was performed using pooled samples. Given the heterogeneity of studies and results reporting, a standard meta‐analysis for comparing studies with paired samples and a weighted average was not feasible.

Risk of Bias Assessment

Bias of publication was assessed for each included article with the Mixed Methods Appraisal Tool (MMAT). 10 Evaluated domains included: participant selection, randomization, assessor blinding, adherence to intended intervention, completeness of data, and outcome measurement. The series of questions to assess bias within the tool were answered based on article type for each included study.

RESULTS

Search Results

A total of 44 studies met criteria for inclusion. A description of the participants, interventions, comparisons, outcomes, timing, and study design (PICOTS) of included ototoxic publications is shown in Table I . 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 Table S1 summarizes reasons for exclusion during literature search and review.

Assessment of Bias

Bias was assessed using the MMAT. The studies included in this review were considered to have a relevant sampling strategy and be representative of the target population. The largest proportion of included articles (79.5%) reported on quantitative descriptive studies (Table II ). The distribution of affirmative responses to the MMAT categories indicate a generally high quality within the framework of their respective designs. The assessment results are detailed in Table II .

Patient and Study Characteristics

The 44 included studies consisted of 31 case reports or series, two prospective cohort studies, three retrospective cohort studies, one open‐label trial, one randomized controlled trial, one pooled analysis and five database analyses. Twenty‐nine of the 44 studies only included patients who reported adverse otologic symptoms and 15 reported all patients who took the monoclonal antibody, regardless of ototoxic symptoms. Across the 44 included studies, a total of 18,046 patients were treated with mABs and noted to have hearing‐related symptoms and audiometric findings while taking the medication. Thirty‐one of the 44 studies reported obtaining audiometric data, with 23 of those providing either the results of WRS/SRT testing or the audiograms directly, and only seven studies including baseline audiometric evaluations. Where demographic information was provided by included studies, the mean age of patients assessed across studies was 57.8 years old and comprised of 3335 females. Characteristics of included patients, where reported, are summarized in Table III . Table IV reports the quantitative data available across the included studies.

Outcomes of Ototoxicity

The search yielded 18 agents across 44 studies reported to have ototoxic symptoms, inclusive of a total sample size of 18,046 patients. Symptoms of ototoxicity occurred in 1079 patients. Of these patients, 524 were identified from studies that only reported patients who experienced ototoxicity after treatment with a monoclonal antibody (i.e., case reports of hearing loss after treatment). Conversely, 555 of the patients who experienced ototoxicity came from studies that included all patients treated by a monoclonal antibody, regardless of ototoxic side effect. Agents causing ototoxicity included teprotumumab ( n = 17/44 studies), nivolumab ( n = 10/44), ipilimumab ( n = 9/44), pembrolizumab ( n = 5/44), and rituximab ( n = 4/44), adalimumab ( n = 3/44), and infliximab ( n = 2/44). Additional reported agents included abatacept, daratumumab, erenumab, etanercept, fremanezumab, mepolizumab, muronumab, nimotuzumab, omalizumab, panitumumab, and trastuzumab ( n = 1/44 each).

Thirty‐one of 44 studies encompassing eight agents (infliximab, teprotumumab, ipilimumab, nivolumab, pembrolizumab, muronumab, rituximab, etanercept) reported audiometric data for ototoxic agents, showing sensorineural hearing loss (SNHL) primarily in the high‐frequency range. Seven of the 31 studies, evaluating etanercept, infliximab, and teprotumumab, reported performing an audiogram prior to the start of treatment as well as after the onset of monoclonal antibody‐related ototoxic symptoms. Twenty‐four studies performed audiometric testing only at the onset of symptomatology, assessing infliximab, ipilimumab, muronumab, nivolumab, rituximab, pembrolizumab, and teprotumumab. Only two of 31 articles performed ultrahigh‐frequency audiograms, both of which were reported with teprotumumab. None of the studies scheduled regular audiometric testing during treatment with the monoclonal antibody, regardless of symptomatology. Studies involving abatacept, adalimumab, daratumumab, erenumab, fremanezumab, nimotuzumab, mepolizumab, omalizumab, panitumumab, and trastuzumab did not perform audiometric data collection, with only subjective reporting of symptoms. Systemic and/or intratympanic steroids were used for treatment of hearing loss in 23 studies, with partial or complete recovery reported in 17 studies, though only 15 of which reported audiometric data. Notably, Touma et al. denoted in their case series of two patients that one patient experienced audiogram improvement with infliximab, whereas another experienced audiogram deterioration with infliximab. 47

Ototoxic agent quantitative data represented across included studies are detailed in Table V . ASHA guidelines for medication‐induced ototoxicity are denoted as a 20 dB threshold decrease at any frequency, 10‐dB decrease at any two consecutive frequencies, or no response at three consecutive frequencies where responses were previously present. The following ototoxic agents met one of these criteria: pembrolizumab, nivolumab, rituximab, ipilimumab, teprotumumab, and muronumab. 9 Ototoxic agents represented across included studies, their indications, mechanism of action, mechanism of ototoxicity, and methods of administration are detailed in Table VI . 54 , 55 , 56 , 57

DISCUSSION

In this review, we present an assessment of monoclonal antibody usage that has resulted in otologic symptoms and reported impact on hearing function. We additionally review each agent's postulated mechanism of action, where available in the literature. Of the 18 agents represented, there were a variety of indications represented, many of which are conditions traditionally managed or comanaged by otolaryngologists. For example, teprotumumab, used in the treatment of thyroid eye disease was the most represented ototoxic agent with 17 out of 44 studies discussing its effects. In addition to the currently published case reports and series, multicenter studies are beginning to emerge echoing these observations of ototoxic adverse events with IGF‐1R pathway inhibition, including Shah et al. who reported patients discontinuing teprotumumab therapy due to hearing loss. The FDA warning label of teprotumumab added risk of hearing impairment in July 2023. 44 , 58 Nivolumab and ipilimumab, involved in T‐cell modulation as a PD‐1 inhibitor and CTLA‐4 inhibitor, respectively, were represented in roughly one‐quarter of ototoxic studies. Like teprotumumab, both of these agents have come under increasing scrutiny for ototoxic adverse events, as discussed in Naples et al.'s review of ototoxic agents. 59

Notably, a select number of monoclonal antibodies have been noted in the literature to be implicated both in ototoxicity and potential therapeutic benefit—TNFα inhibitors like etanercept, golimumab, and infliximab. 60 , 61 , 62 , 63 These agents have been reported to have protective otologic effects for patients afflicted with hearing loss as a result of autoimmune inner ear disease (AIED). The case report by André et al. noted improvement with infliximab therapy in a patient's episodes of bilateral deafness that was refractory to prior attempts of treating with steroids, azathioprine, mycophenolate mofetil, and cyclosporine. 60 The patient's deafness was suspected to have an underlying inflammatory or autoimmune mechanism. Derebery et al. conducted an open‐label trial with golimumab for AIED. 61 Heywood et al. similarly shared a case report of successful AIED treatment with infliximab. 62 Matteson et al.'s open‐label trial found mild efficacy of etanercept in the treatment of immune‐mediated cochleovestibular disorders (IMCVDs) and patients with symptoms of bilateral Meniere's disease. 63 For these mABs, it appears a balance may exist between reduction in TNFα mediated‐inflammatory processes and hypersensitivity‐type vasculitis reactions mediated by TNFα immunocomplexes. Additionally, Plotkin et al. report the utility of bevacizumab in treating hearing loss for patients with neurofibromatosis 2. 64 Rituximab has similarly been reported to have beneficial effects in the treatment of AIED by resolving symptoms of hearing loss. 65 In these studies, indications for audiometric evaluation, where reported, included assessment of symptomatic hearing loss for infliximab, and per study protocol for bevacizumab, etanercept, and golimumab. Further study is needed to ascertain the optimal dosing of such agents to minimize adverse reactions and maximize therapeutic benefit. Additionally, although these reactions may largely be sporadic in nature, investigation to understand which of the anti‐CD20 agents and TNFα inhibitors are more prone to these unfavorable complications than others can further optimize their potentially therapeutic effects for patients.

Agents such as those reviewed in this article pose challenging decisions to providers in the balance of therapeutic benefit and unforeseen adverse effects. Some agents have strong evidence underlying their effects, although others can have a dichotomous response with ototoxic implications as well as a potentially positive impact in immune‐modulated SNHL. Many monoclonal antibodies may be originally prescribed by other specialists, such as those used for the treatment of melanoma or lung cancer, which may leave otolaryngologists to wrestle with the balance of harm and benefit by discontinuing therapy in the setting of adverse events. Others, such as teprotumumab, may place some otolaryngologists in the unique position of reconciling between the two conditions at hand. As the medication class of monoclonal antibodies continues to quickly expand, otolaryngologists may be increasingly called upon to weigh in on such effects from the academic to community level.

As shown in Table VI , there exist a myriad of postulated mechanisms of these events, but each relates to the intracochlear immune response. Otolaryngologists should remain mindful of this cochlear immune mechanism, and there exists an opportunity for otolaryngologists to educate colleagues and patients in regard to the relationship of the immune response within the inner ear. Currently, no clear pattern or definitive paradigm exists for adverse events with monoclonal antibodies and their management, as these agents have been implicated in both steroid‐ and nonsteroid‐responsive immune‐mediated hearing loss. The impact of hearing symptoms must be contextualized to the nature and severity of both the otologic effects and the underlying indication for mAB treatment. However, most of the existing reports remain subjective and unaccompanied by objective audiometric testing. Collaboration between otolaryngologists and audiologists should be encouraged in the management of these emerging symptoms, and as a field, it is critical to continue encouragement of formal, robust analysis of these ototoxic events in both industry and academia to help guide clinical assessment.

There are limitations to be noted with this work. From a demographics standpoint, the representation of female patients within the sample is not aligned with that of the general population. Regarding the results, audiometric data were not consistently available, limiting the quantifiable assessments, meta‐analysis, and cross‐comparison of effects that could be performed across agents. The methodology by which ototoxicity is defined remains heterogenous, and as the usage of these agents continues to expand, there is a need to standardize the metrics employed in assessment and reporting of events with monoclonal antibodies that have the potential for otologic effects. Ideally, audiometric data should be recorded prior to the start of treatment and periodically throughout the course of therapy. Should ototoxic symptoms present, data should additionally be obtained following drug cessation and/or treatment with steroids to assess return to baseline audiometry. Ultrahigh‐frequency (>8 kHz) audiograms, in particular, should be performed for optimal characterization of hearing deficits if present, as serial hearing assessment at the highest audible frequencies using these thresholds allows early detection of ototoxicity before speech frequencies are impaired. 66 Consistent monitoring should be encouraged for ototoxic symptoms by both patients and providers. Further work should additionally involve deeper investigation into the underlying mechanisms employed by each agent to produce ototoxicity. While many of the agents discussed in this review have postulated mechanisms of action reported in the literature, a number remain whose mechanisms have yet to be characterized. Ultimately, this review underscores the need for a greater collection of concrete and quantifiable data to build the body of knowledge pertaining to the toxicity of immunomodulatory agents.

CONCLUSION

As monoclonal antibody usage continues to expand, it is critical to understand their broader implications and adverse effects. This review highlights a wide variety of immunomodulatory agents that have been reported as having potential for ototoxicity. However, testing of such effects remains heterogeneous and further audiometric assessment under standardized conditions is required to fully characterize the effects of these therapies. Nevertheless, providers should be aware of these potential symptoms as they encounter patients undergoing treatment with this expanding class of medications.

Supporting information

Table S1. Reasons for study exclusion.

Editor's Note: This Manuscript was accepted for publication on August 28, 2024.

This article was presented at the Triological Society meeting at the Combined Otolaryngology Spring Meetings (COSM) in Chicago, Illinois, USA; May 15–19, 2024.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

BIBLIOGRAPHY

1. Monoclonal antibodies. LiverTox: Clinical and Research Information on Drug‐Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2024.

2. Bradbury ARM, Sidhu S, Dübel S, McCafferty J. Beyond natural antibodies: the power of in vitro display technologies. Nat Biotechnol. 2011;29(3):245‐254. 10.1038/NBT.1791.

3. Baldo BA. Immune‐ and non‐immune‐mediated adverse effects of monoclonal antibody therapy: a survey of 110 approved Antibodies. Antibodies. 2022;11(1):17. 10.3390/antib11010017.

4. Belinsky I, Creighton FX Jr, Mahoney N, et al. Teprotumumab and hearing loss: case series and proposal for audiologic monitoring. Ophthal Plast Reconstr Surg. 2022;38(1):73‐78. 10.1097/IOP.0000000000001995.

5. McKeage K, Perry CM. Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs. 2002;62(1):209‐243. 10.2165/00003495-200262010-00008.

6. Ganesan P, Schmiedge J, Manchaiah V, Swapna S, Dhandayutham S, Kothandaraman PP. Ototoxicity: a challenge in diagnosis and treatment. J Audiol Otol. 2018;22(2):59‐68. 10.7874/jao.2017.00360.

7. Moher D, Liberati A, Tetzlaff J, Altman DG; Group TP . Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. 10.1371/journal.pmed.1000097.

8. Haddaway NR, Page MJ, Pritchard CC, McGuinness LA. PRISMA2020: an R package and shiny app for producing PRISMA 2020‐compliant flow diagrams, with interactivity for optimised digital transparency and open synthesis. Campbell Syst Rev. 2022;18:e1230. 10.1002/cl2.1230.

9. Lord SG. Monitoring protocols for Cochlear toxicity. Semin Hear. 2019;40(2):122‐143. 10.1055/S-0039-1684042.

10. Hong Q, Pluye P, Fabregues S, et al. Mixed Methods Appraisal Tool (MMAT) version 2018 for information professionals and researchers. Education for information. 2018;34(4):285‐291.

11. Barbieri MA, Cicala G, Cutroneo PM, et al. Ototoxic adverse drug reactions: a disproportionality analysis using the Italian spontaneous reporting database. Front Pharmacol. 2019;10:1161. 10.3389/fphar.2019.01161.

12. Choi JS, Chen M, McQuade JL, Appelbaum E, Gidley PW, Nader ME. Recurrent audiovestibular dysfunction and associated neurological immune‐related adverse events in a melanoma patient treated with nivolumab and ipilimumab. Head Neck. 2020;42(11):E35‐E42. 10.1002/hed.26455.

13. Chow A, Silkiss RZ. Teprotumumab‐associated chronic hearing loss screening and proposed treatments. BMJ Case Rep. 2022;15(4):e248335. 10.1136/bcr-2021-248335.

14. Conway R, Khan S, Foley‐Nolan D. Use of adalimumab in treatment of autoimmune sensorineural hearing loss: a word of caution. J Rheumatol. 2011;38(1):176. 10.3899/jrheum.100593.

15. Douglas RS, Couch S, Wester ST, et al. Efficacy and safety of teprotumumab in patients with thyroid eye disease of long duration and low disease activity. J Clin Endocrinol Metab. 2023;109(1):25‐35. 10.1210/clinem/dgad637.

16. De Groot M, Compter A, De Langen AJ, Brandsma D. Susac's syndrome as an immune‐related adverse event after pembrolizumab: a case report. J Neurol. 2020;267(1):282‐284. 10.1007/s00415-019-09587-4.

17. Ding AS, Mahoney NR, Campbell AA, Creighton FX. Sensorineural hearing loss after teprotumumab therapy for thyroid eye disease: a case report. Otol Neurotol. 2022;43(2):e148‐e152. 10.1097/MAO.0000000000003428.

18. Favrelière S, Delaunay P, Lebreton JP, et al. Drug‐induced hearing loss: a case/non‐case study in the French pharmacovigilance database. Fundam Clin Pharmacol. 2020;34(3):397‐407. 10.1111/fcp.12533.

19. Gambichler T, Seifert C, Lehmann M, Lukas C, Scheel C, Susok L. Concurrent Vogt‐Koyanagi‐Harada disease and impressive response to immune checkpoint blockade in metastatic melanoma. Immunotherapy. 2020;12(7):439‐444. 10.2217/imt-2019-0206.

20. Grisariu S, Vaxman I, Gatt M, et al. Enteroviral infection in patients treated with rituximab for non‐Hodgkin lymphoma: a case series and review of the literature. Hematol Oncol. 2017;35(4):591‐598. 10.1002/hon.2365.

21. Hartnick CJ, Cohen AF, Smith RV. Reversible sensorineural hearing loss after renal transplant immunosuppression with OKT3 (muromonab‐CD3). Ann Otol Rhinol Laryngol. 1997;106(8):640‐642. 10.1177/000348949710600804.

22. Healy EG, Phadke R, Kidd M, Reilly MM, Lunn MP. Clinical, neuropathological and radiological evidence for a rare complication of rituximab therapy. Neuromuscul Disord. 2015;25(7):589‐592. 10.1016/j.nmd.2015.04.004.

23. Highland J, Gordon S, Reddy D, Patel N. Ototoxicity and teprotumumab. Ann Otol Rhinol Laryngol. 2022;131(8):910‐913. 10.1177/00034894211042740.

24. Hobelmann K, Fitzgerald D. A case of pembrolizumab induced autoimmune sensorineural hearing loss. J Otol Rhinol. 2019;8(1).

25. Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off‐treatment follow‐up results from two randomised, double‐masked, placebo‐controlled, multicentre trials. Lancet Diabetes Endocrinol. 2021;9(6):360‐372. 10.1016/S2213-8587(21)00056-5.

26. Kay‐Rivest E, Belinsky I, Kozlova A, Byrd E, McMenomey SO, Jethanamest D. Prospective assessment of otologic adverse events due to teprotumumab: preliminary results. Otolaryngol Head Neck Surg. 2023;168(5):1164‐1169. 10.1002/ohn.174.

27. Keen JA, Correa T, Pham C, et al. Frequency and patterns of hearing dysfunction in patients treated with teprotumumab. Ophthalmology. 2024;131(1):30‐36. 10.1016/j.ophtha.2023.08.001.

28. Lemasson J, Cuzzubbo S, Doucet L, et al. Cochleovestibular toxicity induced by immune checkpoint inhibition: a case series. Eur J Cancer. 2019;117:116‐118. 10.1016/j.ejca.2019.05.022.

29. Lu TJ, Amarikwa L, Winn BJ, Inserra M, Dosiou C, Kossler AL. Oral corticosteroids for teprotumumab‐related hearing loss: a case report. Case Rep Ophthalmol. 2023;14(1):134‐139. 10.1159/000529422.

30. Men CJ, Amarikwa L, Pham B, et al. Teprotumumab for the treatment of recalcitrant thyroid eye disease. Ophthal Plast Reconstr Surg. 2024;40(3):276‐285. 10.1097/IOP.0000000000002564.

31. Monferrer‐Adsuara C, Hernández‐Bel L, Hernández‐Garfella ML, et al. Case report: ipilimumab‐induced multisystem autoimmune‐like toxicities suggestive of Vogt‐Koyanagi‐Harada‐like syndrome. Optom Vis Sci. 2021;98(11):1309‐1316. 10.1097/OPX.0000000000001798.

32. Nagai R, Yamamoto A, Yoshida A, Mikawa A. Outcome of nivolumab‐induced Vogt‐Koyanagi‐Harada disease‐like uveitis in a patient managed without intravenous methylprednisolone therapy. Case Rep Ophthalmol Med. 2023;2023:9565205. 10.1155/2023/9565205.

33. Najjar W, Yu J. Audiologic demonstration of ototoxicity from teprotumumab treatment in a patient with thyroid eye disease. OTO Open. 2022;6(2):2473974X221097097. 10.1177/2473974X221097097.

34. Page JC, Gidley PW, Nader ME. Audiovestibular toxicity secondary to immunotherapy: case series and literature review. J Immunother Precis Oncol. 2022;5(1):2‐6. 10.36401/JIPO-21-17.

35. Park HT, Park S, Jung YW, Choi SA. Is omalizumab related to ear and labyrinth disorders? A disproportionality analysis based on a global pharmacovigilance database. Diagnostics. 2022;12(10):2434. 10.3390/diagnostics12102434.

36. Phansalkar R, Lu T, Alyono J, Lee J, Dosiou C, Kossler AL. Reduction of teprotumumab‐induced hearing loss with comparable efficacy using half‐dose therapy. Ophthal Plast Reconstr Surg. 2023;39(4):e101‐e104. 10.1097/IOP.0000000000002355.

37. Rajapakse A, O'Leary C, Gundelach R, Deva R, O'Byrne K. Unilateral autoimmune inner ear disease in a patient with lung cancer treated with nivolumab. Oxf Med Case Reports. 2020;2020(9):omaa077. 10.1093/omcr/omaa077.

38. Ray JC, Allen P, Bacsi A, et al. Inflammatory complications of CGRP monoclonal antibodies: a case series. J Headache Pain. 2021;22(1):121. 10.1186/s10194-021-01330-7.

39. Reed DS, Kostosky N, Davies BW, Epstein A, Durairaj VD. Rifle blast exacerbating hearing loss in a patient treated with teprotumumab for thyroid eye disease. Ophthal Plast Reconstr Surg. 2022;38(2):e41‐e43. 10.1097/IOP.0000000000002078.

40. Rosner S, Agrawal Y, Sun DQ, et al. Immune‐mediated ototoxicity associated with immune checkpoint inhibitors in patients with melanoma. J Immunother Cancer. 2020;8(2):e001675. 10.1136/jitc-2020-001675.

41. Savastano M, Marioni G, Giacomelli L, Ramonda R, Ferraro SM, Punzi L. Sensorineural hearing loss in ankylosing spondylitis treated with TNF blockers. B‐ENT. 2010;6(3):183‐188.

42. Schlacter JA, Kay‐Rivest E, McMenomey SO, Roland JT Jr, Friedmann DR, Jethanamest D. Bilateral cochlear implantation after immunotherapy‐related profound hearing loss: a case report. Cochlear Implants Int. 2023;24(5):268‐272. 10.1080/14670100.2023.2193918.

43. Sears CM, Azad AD, Amarikwa L, et al. Hearing dysfunction after treatment with teprotumumab for thyroid eye disease. Am J Ophthalmol. 2022;240:1‐13. 10.1016/j.ajo.2022.02.015.

44. Shah SA, Amarikwa L, Sears CM, et al. Teprotumumab‐related adverse events in thyroid eye disease: a multicenter study. Ophthalmology. 2024;131(4):458‐467. 10.1016/j.ophtha.2023.10.018.

45. Stürmer SH, Lechner A, Berking C. Sudden otovestibular dysfunction in 3 metastatic melanoma patients treated with immune checkpoint inhibitors. J Immunother. 2021;44(5):193‐197. 10.1097/CJI.0000000000000367.

46. Tampio AJF, Dhanireddy S, Sivapiragasam A, Nicholas BD. Bilateral sensorineural hearing loss associated with nivolumab therapy for stage IV malignant melanoma. Ear Nose Throat J. 2021;100(3_suppl):286S‐291S. 10.1177/0145561320940847.

47. Touma Z, Nawwar R, Hadi U, Hourani M, Arayssi T. The use of TNF‐alpha blockers in Cogan's syndrome. Rheumatol Int. 2007;27(10):995‐996. 10.1007/s00296-007-0373-y.

48. Voskens C, Cavallaro A, Erdmann M, et al. Anti‐cytotoxic T‐cell lymphocyte antigen‐4‐induced regression of spinal cord metastases in association with renal failure, atypical pneumonia, vision loss, and hearing loss. J Clin Oncol. 2012;30(33):e356‐e357. 10.1200/JCO.2011.41.4359.

49. Yu CY, Correa T, Simmons BA, Hansen MR, Shriver EM. Audiology findings in patients with teprotumumab associated otologic symptoms. Am J Ophthalmol Case Rep. 2021;24:101202. 10.1016/j.ajoc.2021.101202.

50. Yun X, Zhou Y, Wu D, Liu Y, Wu Q. A real‐world pharmacovigilance study of FDA adverse event reporting system events for daratumumab. Expert Opin Drug Saf. 2024;23(5):581‐591. 10.1080/14740338.2024.2328321.

51. Zhang S, Huang X, Zhou L, et al. An open‐label, single‐arm phase II clinical study of induction chemotherapy and sequential Nimotuzumab combined with concurrent chemoradiotherapy in N3M0 stage nasopharyngeal carcinoma. J BUON. 2018;23(6):1656‐1661.

52. Zhang S, Wang Y, Qi Z, Tong S, Zhu D. Data mining and analysis of adverse event signals associated with teprotumumab using the Food and Drug Administration adverse event reporting system database. Int J Clin Pharmacol. 2024;46(2):471‐479. 10.1007/s11096-023-01676-9.

53. Zibelman M, Pollak N, Olszanski AJ. Autoimmune inner ear disease in a melanoma patient treated with pembrolizumab. J Immunother Cancer. 2016;4:8. 10.1186/s40425-016-0114-4.

54. Mohamed Ahamada M, Wu X. Analysis of efficacy and safety of abatacept for rheumatoid arthritis: systematic review and meta‐analysis. Clin Exp Rheumatol. 2023;41(9):1882‐1900. 10.55563/clinexprheumatol/2xjg0d.

55. Keating GM. Panitumumab: a review of its use in metastatic colorectal cancer. Drugs. 2010;70(8):1059‐1078. 10.2165/11205090-000000000-00000.

56. Franz L, Frosolini A, Parrino D, Lovato A, de Filippis C, Marioni G. Ototoxicity of immunosuppressant drugs: a systematic review. J Int Adv Otol. 2022;18(2):167‐176. 10.5152/iao.2022.21416.

57. Eryılmaz A, Demirci B, Günel C, et al. Evaluation of lapatinib and trastuzumab for ototoxic effects. J Int Adv Otol. 2015;11(3):207‐211. 10.5152/iao.2015.912.

58. Horizon Therapeutics . Tepezza prescribing information. Accessed August 5, 2024. https://www.hzndocs.com/TEPEZZA-Prescribing-Information.pdf .

59. Naples JG, Rice‐Narusch W, Watson NW, et al. Ototoxicity review: a growing number of non‐platinum‐based chemo‐ and immunotherapies. Otolaryngol Head Neck Surg. 2023;168(4):658‐668. 10.1177/01945998221094457.

60. André R, Corlieu P, Crabol Y, Cohen P, Guillevin L. Infliximab reverses progressive deafness. Presse Med. 2015;44(6 Pt 1):675‐677. 10.1016/j.lpm.2015.02.014.

61. Derebery MJ, Fisher LM, Voelker CC, Calzada A. An open label study to evaluate the safety and efficacy of intratympanic golimumab therapy in patients with autoimmune inner ear disease. Otol Neurotol. 2014;35(9):1515‐1521. 10.1097/MAO.0000000000000566.

62. Heywood RL, Hadavi S, Donnelly S, Patel N. Infliximab for autoimmune inner ear disease: case report and literature review. J Laryngol Otol. 2013;127(11):1145‐1147. 10.1017/S002221511300217X.

63. Matteson EL, Choi HK, Poe DS, et al. Etanercept therapy for immune‐mediated cochleovestibular disorders: a multi‐center, open‐label, pilot study. Arthritis Rheum. 2005;53(3):337‐342. 10.1002/art.21179.

64. Plotkin SR, Stemmer‐Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361(4):358‐367. 10.1056/NEJMoa0902579.

65. Balouch B, Meehan R, Suresh A, et al. Use of biologics for treatment of autoimmune inner ear disease. Am J Otolaryngol. 2022;43(5):103576. 10.1016/j.amjoto.2022.103576.

66. Konrad‐Martin D, Gordon Jane S, Reavis Kelly M, Wilmington Debra J, Helt Wendy J, Fausti SA. Audiological monitoring of patients receiving ototoxic drugs. Perspect Hear Hear Disord Res Res Diagn. 2005;9(1):17‐22. 10.1044/hhd9.1.17.

Associated Data

Supplementary Materials

Table S1. Reasons for study exclusion.