Otological aspects of NLRP3-related autoinflammatory disorder focusing on the responsiveness to anakinra

Abstract

Objectives Gradually progressive sensorineural hearing loss (SNHL) is a prevalent sensory defect. It is generally untreatable, making rehabilitation by hearing aid or cochlear implantation the only option. However, SNHL as one of the symptoms of the hereditary autoinflammatory systemic disease cryopyrin-associated periodic syndrome, or as the only symptom of the cochlea-specific form (DFNA34), was suggested to respond to IL-1 antagonist (anakinra) therapy, which ameliorates NLRP3 variants-induced over-secretion of IL-1β. We analysed genotypic and phenotypic spectrum of cryopyrin-associated periodic syndrome or DFNA34, specifically focusing on the responsiveness of SNHL to anakinra. Methods Seventeen families diagnosed with either cryopyrin-associated periodic syndrome or DFNA34 were recruited. Genotyping and phenotyping including audiogram, MRI findings, and in vitro IL-1β assay were performed. Results Our cohort had an etiologic homogeneity of 94.1% to NLRP3 variants and a high de novo occurrence (84.6%). We identified the second DNFA34 pedigree worldwide with a novel NLRP3 variant supported by in vitro analysis. Significant improvement of hearing status against the natural course, showing response to anakinra, was identified in three probands, one of whom used to have severe SNHL. Hearing threshold worse than 60 dB at the start of anakinra and cochlear enhancement on brain MRI seemed to be related with poor audiologic prognosis and responsiveness to anakinra therapy despite stabilized systemic symptoms and inflammatory markers. Conclusion We propose a constellation of biomarkers comprising NLRP3 genotypes, hearing status at diagnosis, and cochlear radiological findings as prognostic factors of hearing status after anakinra treatment and possibly as sensitive parameters for treatment dosage adjustment.

Hearing Loss as the Main Clinical Presentation in NLRP3-Associated Autoinflammatory Disease

“…A strong argument in favor of cochlear inflammation being causally involved in the development of HL in NLRP3-AID, is the pathological enhancement visible on the MRI post-contrast FLAIR images of the cochlea. Enhancement indicates that the contrast material has diffused into cochlear tissues from the blood vessels, made more permeable by inflammation (15). In previous studies and in our patients, pathological cochlear enhancement has been associated with the presence of HL (16,19).…”

“…This was also the case for the family reported in this study, although the age at HL onset, the severity of hearing deterioration, and its rate of progression vary among NLRP3-AID patients. The onset of HL may range from the first months to the fourth decade of life, and individuals can have severe to profound HL (15,17). In the family described here, the onset of HL was after 15 years of age and HL had progressed over time.…”

“…Overproduction of IL-1b, considered the central mediator of inflammation, plays a main role in the pathogenesis of NLRP3-AID; consequently, treatment with anti-IL-1 receptor inhibitors such as anakinra or canakinumab is recommended for this group of patients (5). A positive therapeutic effect on hearing (such as its stabilization in the majority of patients or improvement in some individuals) has also been achieved, especially when treatment is begun early (15,(19)(20)(21)(22)(23). Poor response to anti-IL-1 receptor inhibitors is likely explained by a chronic inflammation that has already caused irreversible cochlear damage.…”

“…In contrast, the two gene variants detected in the DFNA34 patients locate more toward the 3′ end (Figure 2) which encodes the LRR domain. Based on previous findings, it has been proposed that the NLRP3 pathogenic variants affecting the LRR domain might be related to a milder phenotype (2,15); this proposal might be expanded to indicate that the milder phenotype is also observed for NLRP3 mutations affecting other parts of the gene. In summary, the results of our study highlight the need to perform genetic testing in patients with HL.…”

Genetic Information and Precision Medicine in Hearing Loss

“…In contrast, variants of DFNB59 and PCDH15 have been associated with a poor prognosis after CI [13]. Interestingly, a subset of patients with autoinflammatory inner ear diseases can show improvement of nonsyndromic HL if they carry an NLRP3 variant and receive anakinra treatment [16,17].…”