The field of autoimmunity is evolving to include a whole new set of conditions called autoinflammatory diseases, some of which include sensorineural deafness among their symptoms, according to new research by Andrea Vambutas, MD, chair of otolaryngology at Long Island Jewish Medical Center and North Shore University Medical Center in New York.
Dr. Vambutas, an active clinician and professor of otolaryngology and molecular medicine at the Zucker School of Medicine at Hofstra/Northwell, is also an investigator in the Center for Autoimmune, Musculoskeletal, and Hematopoietic Diseases at the Feinstein Institutes for Medical Research. She delivered the Howard P. House Memorial Lecture for Advances in Otology on September 17, 2019 at the American Academy of Otolaryngology–Head and Neck Surgery Annual Meeting on key biologic and clinical features that distinguish autoimmune from autoinflammatory disease and covered new treatment possibilities in the pipeline for sensorineural deafness.
Autoimmune and allergic disorders are on the rise. According to Dr. Vambutas’ presentation, these include more than 80 distinct diseases and affect 14 to 23 million people. When it comes to immune-mediated hearing loss—for example, in the case of Meniére’s disease, sudden sensorineural hearing loss (SSNHL), or autoimmune inner ear disease (AIED) —the challenge clinicians face is that there is no specific diagnostic biologic marker to show the severity of disease, how it should be treated, or for how long.
Autoimmune or Autoinflammatory?
Understanding autoimmune and autoinflammatory disease requires knowing the difference between the innate and the adaptive immune response. According to the presentation, when the innate immune system works, the macrophages come in first and present antigen to the adaptive immune response. Autoinflammatory disease occurs when the innate immune response isn’t working. Autoimmune disease occurs when the adaptive immune response isn’t working.
The triggers for these rare diseases are largely unknown but may include genetic predisposition, allergy, or even acoustic trauma. Although autoinflammatory diseases are genetic, no genetic marker for AIED has been identified, and patients do not typically have afflicted relatives. The clinical treatment history for patients with these conditions has been limited to prednisone; methotrexate and TNF antagonists have limited efficacy. Of the 60% of patients who initially respond to steroid treatment, only 14% remain responsive after 34 months, and those patients are at risk for side effects that can range from osteoporosis to psychosis. Steroid-resistant patients have been limited to rehabilitative strategies such as hearing aids and cochlear implants, because no medical therapy has been shown to be effective.
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.”
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.
Renée Bacher is a freelance medical writer based in Louisiana.