IL-1ß is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.

Autoimmune inner ear disease is an enigmatic disorder characterized by recurring episodes of sudden or progressive sensorineural hearing loss. Hearing loss can be improved by timely corticosteroid administration, but only half of those treated respond, and for many responders, that response is lost over time. The mechanisms that control corticosteroid responsiveness in this disorder are largely uncharacterized. We have previously identified that the induction by dexamethasone of IL-1R type II (IL-1R2) expression in PBMC predicts corticosteroid responsiveness in this disorder. In this study, we asked whether IL-1ß was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1ß expression or release in response to dexamethasone, as compared with nonresponders. IL-1ß has been reported to induce matrix metalloproteinase-9 (MMP-9) expression. Given that metalloproteinases can cleave IL-1R2, we also asked whether MMP-9 expression was altered in this disorder. In this study, we demonstrate that corticosteroid nonresponders have elevated plasma levels of IL-1ß and MMP-9 as compared with clinically responsive patients (p = 0.0008 and p = 0.037, respectively). Increasing MMP-9 expression correlated with increasing IL-1ß concentration, suggesting that IL-1ß expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1ß. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1ß release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1ß into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1ß release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1ß release, suggesting that IL-1ß blockade may be a viable therapy for these patients.

Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease.

BACKGROUND: Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals. METHODS: We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period. RESULTS: Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1ß plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1ß plasma levels. CONCLUSION: We demonstrated that IL-1ß inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1ß plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1ß inhibition is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01267994. FUNDING: NIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.

Alternate splicing of interleukin-1 receptor type II (IL1R2) in vitro correlates with clinical glucocorticoid responsiveness in patients with AIED.

Autoimmune Inner Ear Disease (AIED) is poorly characterized clinically, with no definitive laboratory test. All patients suspected of having AIED are given glucocorticoids during periods of acute hearing loss, however, only half initially respond, and still fewer respond over time.We hypothesized that AIED is a systemic autoimmune disease characterized by dysfunctional peripheral blood mononuclear cells (PBMC) responses to a unique cochlear antigen(s). To test this hypothesis, we examined end-stage AIED patients undergoing cochlear implant surgery and compared autologous perilymph stimulated PBMC from AIED patients to controls. We determined that autologous perilymph from AIED patients was unable to induce expression of a long membrane-bound Interleukin-1 Receptor Type II (mIL1R2) transcript in PBMC as compared with controls, despite similar expression of the short soluble IL1R2 (sIL1R2) transcript (p<0.05). IL1R2 is a molecular decoy that traps interleukin-1beta (IL-1beta) and does not initiate subsequent signaling events, thereby suppressing an inflammatory response. IL1R2 transcript length is regulated by alternate splicing, and the major inhibitory function is attributed to the full-length mIL1R2. In addition, IL1R2 expression is induced by dexamethasone.Separately, we prospectively examined patients with newer onset glucocorticoid-responsive AIED. Immediately prior to clinical treatment for acute deterioration of hearing thresholds, their PBMC demonstrated a robust induction of mIL1R2 in PBMC in response to dexamethasone in vitro that correlated with a clinical response to prednisone in vivo (p<0.0001) as measured by hearing restoration. In contrast, clinically steroid unresponsive patients demonstrated high basal levels of mIL1R2 in their PBMC and only minimally augmented expression in response to dexamethasone. Thus, induced expression of mIL1R2 appears to be a protective mechanism in hearing homeostasis and warrants further investigation in a large prospective clinical trial to determine if IL1R2 can be used as a specific biomarker for AIED.