Progressive familial hearing loss in Muckle-Wells syndrome.

CONCLUSION: The age-dependent disease progression requires accelerating diagnosis of Muckle-Wells syndrome (MWS) in order to start treatment as early as possible. The most frequent, but not obligate symptoms are familial fatigue, hearing loss, and arthralgia. The design of further clinical trials should focus on hearing in order to document the long-term effect of anti-interleukin (IL)-1 drugs on hearing preservation. OBJECTIVES: This paper describes the otologic features of a genetically defined syndrome causing progressive hearing loss by cochlear degeneration. This is the first study reporting the pretreatment otologic presentation of a selected population with familial MWS. METHODS: A single-center cohort was examined by audiologic and neurotologic methods including pure tone audiograms, vestibular testing, and tinnitus questionnaire. The audiograms of members of the same family were compared to describe the family-specific risk of hearing loss progression. RESULTS: Nineteen patients (aged 3-72 years) belonging to four families with three different mutations of the NLRP3 gene were examined. Almost all patients (89%, 17/19) demonstrated bilateral sensorineural hearing loss. Hearing loss started in the high frequencies and led to profound deafness in the most severe cases. Even in cases of profound hearing loss the vestibular caloric reactivity was normal. Nearly half of the adults reported intermittent or permanent tinnitus.

MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes.

OBJECTIVES: To assess the sensitivity of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 (calprotectin) for monitoring disease activity during anti-interleukin (IL)-1 therapies in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular (CINCA) syndrome. METHODS: A total of 39 patients with CAPS, including 5 FCAS, 16 MWS and 18 CINCA syndrome, received anti-IL-1 therapy. All patients with CINCA and 12 with MWS were treated with IL-1Ra (anakinra), 14 patients with MWS with a monoclonal anti-IL-1ß antibody (canakinumab) and patients with FCAS received IL-1 Trap (rilonacept). During serial clinical visits serum amyloid A, C-reactive protein, erythrocyte sedimentation rate and MRP8/14 serum levels were analysed. RESULTS: Untreated patients with CAPS had significantly elevated MRP8/14 values. In response to treatment there was a significant reduction of MRP8/14 levels in CINCA (2,830 (range 690 - 8,480) ng/ml to 670 ng/ml, p < 0.001) and MWS patients (anakinra-treated: 4,390 (1790 - 9780) ng/ml to 1,315 ng/ml (p = 0.003); canakinumab-treated: 3,000 (500 - 13060) ng/ml to 630 ng/ml (p=0.001)). However, in many patients with CAPS, MRP8/14 levels were still elevated compared with healthy individuals, reflecting residual disease activity. However, canakinumab-treated patients with CAPS showed normalised MRP8/14 levels, suggesting control of phagocyte activation. CONCLUSIONS: Monitoring of cellular systems involved in inflammatory cascades of the innate immunity was successfully applied to the IL-1-driven CAPS diseases. This is the first study illustrating different states of subclinical disease activity in all types of CAPS depending on the type of anti-IL-1 therapy. MRP8/14 is a sensitive biomarker for monitoring disease activity, status of inflammation and response to IL-1 blockade in patients with CAPS.