Advertisement

Intratympanic infliximab is a safe and effective rescue therapy for refractory immune-mediated hearing loss

  • Nieves Mata-CastroEmail author
  • Lorena Sanz-López
  • David Varillas-Delgado
  • Alfredo García-Fernández
Otology
  • 6 Downloads

Abstract

Purpose

To determine the efficacy and safety of the intratympanic infiltration of infliximab at the hearing threshold of patients in follow-up for refractory immune-mediated hearing loss.

Methods

17 patients were collected with relapses, despite maintenance treatment with oral azathioprine associated or not with oral prednisone at low doses (between 5 and 7.5 ml/day) or refractory relapses to previous intratympanic corticoid treatment being 19 affected ears infiltrated. We measured the hearing threshold by Pure-Tone Average (PTA) 500–3000 Hz, 125–8000 Hz and 250–8000 Hz in pre-infiltration (baseline) and follow-up 3 weeks post-infiltration with auditory threshold at frequencies 125–8000 Hz.

Results

The average age was 50.68 years (±15.23 years). After the administration of intratympanic infliximab, an improvement of the hearing threshold was showed in the Pure-Tone Average (PTA) calculated at 500–3000 Hz (p = 0.004), 125–8000 Hz (p = 0.001) and 250–8000 Hz (p = 0.006). An immediate improvement in low frequencies also was observed: 125, 250 and 500 Hz (p = 0.009, p = 0.002 and p < 0.001 respectively) also at 1000 Hz (p = 0.004) and a persistence of the effect at 3 months in the low frequencies: 125 Hz (p = 0.020), 250 Hz (p = 0.006) and 500 Hz (p = 0.002).

Conclusions

Infliximab intratympanic infiltration improves the hearing threshold in patients with immune-mediated hearing loss. The effect of improving the hearing threshold is higher in low frequencies and persists within 3 months of the infiltration. The administration of intratympanic infliximab is an effective and safe technique.

Keywords

Hearing loss Hearing disorders Infliximab Injection intratympanic Audiometry pure tone Auditory threshold 

Notes

Acknowledgements

The authors acknowledge support of physicians and nurses of the Otolaryngology and Rheumatology services of Torrejón Hospital that have collaborated in the attention of the patients of the study.

Author contributions

NMC designed and carried out the study, analysed data and wrote the paper; NMC and LSV designed and performed experiments at the centre in Spain; NMC and LSV collected and analysed data from the centre; NMC, DVD and AGF provided statistical analysis and critical revision. All authors contributed equally to this work. NMC, DVD and AGF reviewed data from all sites and provided interpretive analysis; NMC, LSV and AGF wrote the main paper. All authors discussed the results and implications and commented on the manuscript at all stages.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Hospital research committee (Torrejón Hospital research committee INF-HUT-2019) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Chau JK, Cho JJ, Fritz DK (2012) Evidence-based practice: management of adult sensorineural hearing loss. Otolaryngol Clin North Am 45:941–958CrossRefGoogle Scholar
  2. 2.
    Vambutas A, Pathak S (2016) AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune-Mediated Hearing Loss. Laryngoscope Investig Otolaryngol 1:110–115CrossRefGoogle Scholar
  3. 3.
    Garcia-Berrocal JR, Ibanez A, Rodriguez A, Gonzalez-Garcia JA, Verdaguer JM, Trinidad A, Ramirez-Camacho R (2006) Alternatives to systemic steroid therapy for refractory immune-mediated inner ear disease: a physiopathologic approach. Eur Arch Otorhinolaryngol 263:977–982CrossRefGoogle Scholar
  4. 4.
    Rahman MU, Poe DS, Choi HK (2001) Autoimmune vestibulo-cochlear disorders. Curr Opin Rheumatol 13:184–189CrossRefGoogle Scholar
  5. 5.
    Lobo D, Garcia-Berrocal JR, Trinidad A, Verdaguer JM, Ramirez-Camacho R (2013) Review of the biologic agents used for immune-mediated inner ear disease. Acta Otorrinolaringol Esp 64:223–229CrossRefGoogle Scholar
  6. 6.
    Demirhan E, Eskut NP, Zorlu Y, Cukurova I, Tuna G, Kirkali FG (2013) Blood levels of TNF-alpha, IL-10, and IL-12 in idiopathic sudden sensorineural hearing loss. Laryngoscope 123:1778–1781CrossRefGoogle Scholar
  7. 7.
    Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM (2003) Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation. J Assoc Res Otolaryngol 4:139–147CrossRefGoogle Scholar
  8. 8.
    Fujioka M, Okano H, Ogawa K (2014) Inflammatory and immune responses in the cochlea: potential therapeutic targets for sensorineural hearing loss. Front Pharmacol 5:287CrossRefGoogle Scholar
  9. 9.
    Yoshida K, Ichimiya I, Suzuki M, Mogi G (1999) Effect of proinflammatory cytokines on cultured spiral ligament fibrocytes. Hear Res 137:155–159CrossRefGoogle Scholar
  10. 10.
    Okano T (2014) Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss. Front Pharmacol 5:205CrossRefGoogle Scholar
  11. 11.
    Monaco C, Nanchahal J, Taylor P, Feldmann M (2015) Anti-TNF therapy: past, present and future. Int Immunol 27:55–62CrossRefGoogle Scholar
  12. 12.
    Hess A, Bloch W, Huverstuhl J, Su J, Stennert E, Addicks K, Michel O (1999) Expression of inducible nitric oxide synthase (iNOS/NOS II) in the cochlea of guinea pigs after intratympanical endotoxin-treatment. Brain Res 830:113–122CrossRefGoogle Scholar
  13. 13.
    Warchol ME (1999) Immune cytokines and dexamethasone influence sensory regeneration in the avian vestibular periphery. J Neurocytol 28:889–900CrossRefGoogle Scholar
  14. 14.
    Warchol ME, Kaplan BA (1999) Macrophage secretory products influence the survival of statoacoustic neurons. NeuroReport 10:665–668CrossRefGoogle Scholar
  15. 15.
    Van den Brande JM, Braat H, van den Brink GR, Versteeg HH, Bauer CA, Hoedemaeker I, van Montfrans C, Hommes DW, Peppelenbosch MP, van Deventer SJ (2003) Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 124:1774–1785CrossRefGoogle Scholar
  16. 16.
    Lavigne P, Lavigne F, Saliba I (2016) Intratympanic corticosteroids injections: a systematic review of literature. Eur Arch Otorhinolaryngol 273:2271–2278CrossRefGoogle Scholar
  17. 17.
    Huon LK, Fang TY, Wang PC (2012) Outcomes of intratympanic gentamicin injection to treat Meniere's disease. Otol Neurotol 33:706–714CrossRefGoogle Scholar
  18. 18.
    Van Wijk F, Staecker H, Keithley E, Lefebvre PP (2006) Local perfusion of the tumor necrosis factor alpha blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol Neurootol 11:357–365CrossRefGoogle Scholar
  19. 19.
    Harris JP, Weisman MH, Derebery JM, Espeland MA, Gantz BJ, Gulya AJ, Hammerschlag PE, Hannley M, Hughes GB, Moscicki R, Nelson RA, Niparko JK, Rauch SD, Telian SA, Brookhouser PE (2003) Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial. JAMA 290:1875–1883CrossRefGoogle Scholar
  20. 20.
    Hamid M, Trune D (2008) Issues, indications, and controversies regarding intratympanic steroid perfusion. Curr Opin Otolaryngol Head Neck Surg 16:434–440CrossRefGoogle Scholar
  21. 21.
    Mata-Castro N, Gavilanes-Plasencia J, Ramirez-Camacho R, Garcia-Fernandez A, Garcia-Berrocal JR (2018) Azathioprine reduces the risk of audiometric relapse in immune-mediated hearing loss. Acta Otorrinolaringol Esp 69:260–267CrossRefGoogle Scholar
  22. 22.
    Ghossaini SN, Liu JP, Phillips B (2013) Round window membrane permeability to golimumab in guinea pigs: a pilot study. Laryngoscope 123:2840–2844CrossRefGoogle Scholar
  23. 23.
    Salt AN, Plontke SK (2018) Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications. Hear Res 368:28–40CrossRefGoogle Scholar
  24. 24.
    Plontke SK, Biegner T, Kammerer B, Delabar U, Salt AN (2008) Dexamethasone concentration gradients along scala tympani after application to the round window membrane. Otol Neurotol 29:401–406CrossRefGoogle Scholar
  25. 25.
    Sanz L, Murillo-Cuesta S, Cobo P, Cediel-Algovia R, Contreras J, Rivera T, Varela-Nieto I, Avendano C (2015) Swept-sine noise-induced damage as a hearing loss model for preclinical assays. Front Aging Neurosci 7:7PubMedPubMedCentralGoogle Scholar
  26. 26.
    Wang X, Truong T, Billings PB, Harris JP, Keithley EM (2003) Blockage of immune-mediated inner ear damage by etanercept. Otol Neurotol 24:52–57CrossRefGoogle Scholar
  27. 27.
    Eren SB, Dogan R, Yenigun A, Veyseller B, Tugrul S, Ozturan O, Aydin MS (2017) Evaluation of ototoxicity of intratympanic administration of Methotrexate in rats. Int J Pediatr Otorhinolaryngol 100:132–136CrossRefGoogle Scholar
  28. 28.
    Mata-Castro N, Garcia-Chilleron R, Gavilanes-Plasencia J, Ramirez-Camacho R, Garcia-Fernandez A, Garcia-Berrocal JR (2018) Analysis of audiometric relapse-free survival in patients with immune-mediated hearing loss exclusively treated with corticosteroids. Acta Otorrinolaringol Esp 69:214–218CrossRefGoogle Scholar
  29. 29.
    Lee KY, Nakagawa T, Okano T, Hori R, Ono K, Tabata Y, Lee SH, Ito J (2007) Novel therapy for hearing loss: delivery of insulin-like growth factor 1 to the cochlea using gelatin hydrogel. Otol Neurotol 28:976–981CrossRefGoogle Scholar
  30. 30.
    Yamamoto N, Nakagawa T, Ito J (2014) Application of insulin-like growth factor-1 in the treatment of inner ear disorders. Front Pharmacol 5:208CrossRefGoogle Scholar
  31. 31.
    Martin-Saldana S, Palao-Suay R, Aguilar MR, Ramirez-Camacho R, San Roman J (2017) Polymeric nanoparticles loaded with dexamethasone or alpha-tocopheryl succinate to prevent cisplatin-induced ototoxicity. Acta Biomater 53:199–210CrossRefGoogle Scholar
  32. 32.
    Murillo-Cuesta S, Garcia-Alcantara F, Vacas E, Sistiaga JA, Camarero G, Varela-Nieto I, Rivera T (2009) Direct drug application to the round window: a comparative study of ototoxicity in rats. Otolaryngol Head Neck Surg 141:584–590CrossRefGoogle Scholar
  33. 33.
    Staecker H, Brough DE, Praetorius M, Baker K (2004) Drug delivery to the inner ear using gene therapy. Otolaryngol Clin North Am 37:1091–1108CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of OtolaryngologyHospital Univeristario de TorrejónMadridSpain
  2. 2.Universidad Francisco de Vitoria, Faculty of MedicineMadridSpain
  3. 3.Department of OtolaryngologyHospital Universitario 12 de OctubreMadridSpain
  4. 4.Universidad Complutense, Faculty of MedicineMadridSpain

Personalised recommendations