Background/Purpose: Cryopyrinopathies are autoinflammatory disorders (AID) caused by mutations of NLRP3 gene that lead to interleukin-1 (IL-1) overproduction with the clinical picture of periodic fever. Milder forms as Muckle-Wells syndrome (MWS) can run undiagnosed until adulthood when disease damage (deafness, amyloidosis) may be discovered. We present a observational study of a large family where MWS was diagnosed simultaneously in 4 generations (G). This provides us with the information on the long-term natural disease course followed by systematically documented response to IL-1 blockade.

Methods: Case histories were retrieved from medical records complemented by detailed questioning. Clinical suspicion of MWS was genetically confirmed (c.1322C>T). Patients were followed from the time of diagnosis at 3-monthly intervals by clinical examination, blood and urine tests, patient-reported Auto-Inflammatory Disease Activity Index (AIDAI) and once yearly Autoinflammatory Disease Damage Index (ADDI). Audiometry was performed initially and then in 6-12-monthly intervals. Results of the 2-year follow-up are presented.

Results: Two children in GIV (1.5 and 5 yrs old) presented in infancy with urticarial rash. Their inflammatory markers as well as general condition remained normal and they have not yet required therapy. All 5 affected individuals in GIII (21-33 yrs old) reported frequent attacks of fever, rash, conjunctivitis and arthralgia since pre-school age. They all had raised inflammatory markers and no organ involvement. All responded briskly to daily anakinra. GII has 3 siblings (45, 46, 53 yrs old) all affected (rash, conjunctivitis, arthritis, arthralgia, fever, headaches from pre-school age). Renal amyloidosis was confirmed as a cause of proteinuria and chronic renal failure in patient II/1. Variable degree of sensorineural hearing loss was found in 2 cases. Anakinra led to the rapid improvement of their laboratory activity as well as clinical symptoms. In patient II/1 hearing has remained stable as did his renal function. Audiometry improved by 10-20 dB after 2 years of therapy in patient II/3. Patient I/1 from GI died at 52 years from renal failure. The pre-treatment AIDAI ranged 20-77 points and normalised within 1-3 months in all patients and have remained so. The disease damage noticed in GII expressed by ADDI was 6 (II/1) and 1 (II/3) at the first visit and has remained stable within the follow-up.

Conclusion: Although untreated MWS carries high risk of renal and auditory damage, little is known about the timing of their evolution. The cross-sectional view of untreated disease in 11 patients with the same mutation provides valuable information. Absence of impaired hearing in individuals below 40 years has encouraged us to postpone onset of IL-blockade in the mildly affected children. On the other hand, renal amyloidosis progressed sub-clinically into significant functional impairment in one patient and was a cause of death in another one both in their early fifties. High level of awareness of AIDs and close collaboration between paediatric and adult specialists are the main pre-requisites to optimal management of these rare diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cryopyrinopathy-across-generations-longterm-disease-outcome/