Because there is no single antibody associated with AIED, there are many challenges in treating the condition. Additionally, it’s unclear whether AIED is one disease or many, and animal studies to identify the molecular mechanisms of this disease have been confounding, presenting characteristics never seen in humans. “But the largest remaining issue with which we have not grappled,” said Dr. Vambutas, “is if the progression to autoimmune hearing loss occurs through a toll-like receptor that signals and releases interleukin-1. Toll-like receptors are highly polymorphic. Perhaps, in this room, there are 100 different variations of it. Which one is the right one to study? That’s an area that no one’s really looked into.”
Explore This IssueNovember 2019
Our working hypothesis is that if you have high TNF levels and low IL-1, you’re steroid sensitive, and that if you have high IL-1 beta levels and low TNF, you’re steroid resistant. —Andrea Vambutas, MD
Dr. Vambutas and her colleagues conducted a small clinical trial that looked at patients who did not respond to corticosteroids and treated them with injected anakinra, a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Anakinra is FDA-approved to treat moderate to severely active rheumatoid arthritis. In Dr. Vambutas’ phase I/II trial results, anakinra-treated steroid-resistant patients achieved audiometric improvement relative to standard therapy with steroids.
What the researchers think they have found is that there are two different mechanisms that can cause organ destruction of the inner ear. “There is either the TNF pathway, which is either blocked by corticosteroids, N-acetyl cysteine, or a TNF blockade such as etanercept, or there’s an IL-1 pathway,” she said. “And it’s the critical balance of understanding which pathway is at play at the time of the patient’s presentation with a drop in hearing, and that either pathway signals on to JNK pathway signaling and organ destruction.”
Dr. Vambutas added that there was a recent clinical trial for AM-111 that blocks JNK for sudden sensorineural hearing loss but failed to meet efficacy in a phase 3 trial, indicating that researchers need a better understanding of which patients should be treated given the positive phase 2 data from this trial.
In one six-year clinical case study of a patient taking both prednisone and methotrexate who had previously been unable to wean from either, anakinra made it possible for the patient to finally wean from both without relapse, and preserved his hearing thresholds. He switched to ILARIS, rejected hearing aids, and has been able to hear well enough to graduate from college and enter law school.
“Our working hypothesis is that if you have high TNF levels and low IL-1, you’re steroid sensitive, and that if you have high IL-1 beta levels and low TNF, you’re steroid resistant.” Dr. Vambutas said. “It’s like a light switch, and we just have to figure out where our patient is in that conundrum to figure out what is best to do with them, which is something that we have to work out further and validate our observations in a larger series of patients.
DISCLOSURES: Anakinra and other IL-1 antagonists discussed in this lecture are non-FDA approved for the indication of immune-mediated hearing loss. The studies shown were performed under an IND the researchers obtained; for case one, the drug was used off label. Dr. Vambutas also served on the Scientific Advisory Board for Solvay Pharmaceuticals, which provides drug and placebo for her current clinical trial.