Ssu-Hsien Lee, Lu-Ya Kuo, Tsung-Hsien Tsai
Teprotumumab, the first approved therapy for thyroid eye disease, is highly effective, but has been increasingly associated with otologic adverse events, prompting a United States Food and Drug Administration warning regarding hearing impairment in 2023. Reported incidence varies widely across studies, and the true burden of toxicity remains uncertain. We conducted a systematic review and meta-analysis of PubMed/MEDLINE, Embase, and Cochrane CENTRAL from inception through May, 2026 (PROSPERO CRD420261337579), identifying 22 eligible studies (5 randomized controlled trials and 17 observational studies) comprising 856 teprotumumab-treated patients. The pooled incidence of any otologic adverse event was 27.3% (95% CI, 20.8-34.3%), including subjective hearing loss, tinnitus, aural fullness, and autophony. Clinically significant ototoxicity occurred in 7.7% (95% CI, 3.1-13.8%), while objective audiometric ototoxicity was detected in 20.0% (95% CI, 10.0-32.0%) of patients undergoing serial audiometric monitoring. Compared with placebo, teprotumumab increased the risk of otologic adverse events nearly four-fold (risk ratio, 3.6; 95% CI, 1.3-10.1). Among affected patients, 39.0% (95% CI, 18.0-62.0%) had persistent impairment at last follow-up. Ascertainment method was the major source of between-study heterogeneity, with active surveillance identifying substantially higher event rates than passive reporting (42.0% vs. 20.0%). Preexisting hearing loss, older age, and diabetes were associated with increased risk. Although overlap-adjusted findings were consistent, heterogeneity in design, ascertainment, definitions, and follow-up means these estimates should be regarded as approximate rather than definitive. These results support baseline audiometric assessment, active symptom surveillance during treatment, and informed counseling regarding the potential for persistent hearing impairment. REGISTRATION: PROSPERO CRD420261337579.