The synergistic ototoxicity of adalimumab combined with methotrexate in the treatment of ankylosing spondylitis.

OBJECTIVE

This study aimed to assess the risk of sudden sensorineural hearing loss in patients with ankylosing spondylitis receiving adalimumab in combination with methotrexate, as well as to elucidate the mechanisms underlying drug synergy and ototoxicity.

METHODS

A retrospective analysis was performed on data from 2,564 ankylosing spondylitis patients who were admitted to the department of rheumatology and immunology at Henan Provincial People's Hospital between 2015 and 2024. Fifty-five patients with sudden deafness were designated as the case group, while 110 matched patients without sudden deafness served as the control group. Relevant risk factors were analyzed. Drug exposure was quantified by calculating the defined daily dose (ddd), hearing classification was conducted in accordance with the latest guidelines, and confounding factors were controlled using the inverse probability weighting method (iptw).

RESULT: The case group exhibited a longer duration of ankylosing spondylitis, with an elevated disease activity index, a higher dosage of medications administered, and an extended treatment duration (p < 0.05). The incidence of prior otologic conditions and tinnitus was also significantly higher compared to the control group (p < 0.05). Among the various subtypes of hearing loss, the cumulative drug exposure in patients with total deafness was significantly greater than that in other subtypes (p < 0.05), while patients exhibiting low-frequency decline were more prone to experience tinnitus symptoms. Adalimumab may disrupt the tight junction proteins of the blood-labyrinth barrier, and methotrexate may inhibit mitochondrial folate metabolism in hair cells, thereby synergistically contributing to disturbances in the inner ear microenvironment.

CONCLUSION

The occurrence of sudden deafness in patients treated with the combination of adalimumab and methotrexate for ankylosing spondylitis is associated with drug dosage, treatment duration, and the patient's individual condition. Patients receiving high-dose, long-term therapy and those with a history of otologic conditions are exposed to an increased risk. This study elucidated the synergistic ototoxicity of combination therapy and identified risk factors for sudden deafness in patients with ankylosing spondylitis undergoing treatment with adalimumab and methotrexate, thereby providing a reference for clinical monitoring.