¹Klinik für Nephrologie und Rheumatologie – Universitätsmedizin Göttingen, Klinik für Nephrologie und Rheumatologie, Klinik für Nephrologie und Rheumatologie, Göttingen

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Background: A 72-year-old woman presented to our rheumatological out-patient department with progressive sensorineural hearing loss and multilocular arthralgias. The daughter and two grandchildren of the patient had likewise experienced rapidly progressive hearing loss since childhood. Moleculargenetic panel testing of 242 deafness-associated genes had precedingly revealed a p.Glu313Lys-mutation in NLRP3 in the daughter and grandchildren of the patient. Consecutively, the same mutation was also detected in her, suggesting an autosomal-dominant mode of inheritance.

Main symptom when the disease manifests itself: Upon presentation to our rheumatological out-patient department, the 72-year-old female patient reported long-term hearing loss accompanied by intermittent arthralgic flares of the wrists, ankles and feet. Recurring high fever episodes with influenza-like symptoms occurred regularly. Furthermore, occasional morning stiffness was reported. Sporadic vertigo of undefined nature was described. Ophthalmological examination did not reveal any signs of uveitis nor was there any history of mucocutaneous affection or skin rash.

Diagnostics: On admission, laboratory evaluation presented systemic inflammation with elevated C-reactive protein (CRP 19,1 mg/l) and TNF-alpha levels (twice above the upper limit of normal). Rheumatoid factor (IgG) was detected with otherwise unremarkable results for Rheumatoid factor (IgA and IgM) as well as ANA-IF, complement activity and Il-1B, -2 and -6. Proteinuria was absent in quantitative testing. Liver function tests, ferritin and creatinine fell into the normal range. Initially, serum-amyloid A presented highly elevated (34 mg/l, ref. < 10 mg/l) with marginal elevation of NT-proBNP (191 ng/l, ref. < 125 ng/l). A conducted cardiac MRI scan showed inconclusive results regarding the signs of cardiac A-amyloidosis. A skeletal scintigraphy is currently pending. Arthrosonography of the wrists revealed bilateral arthritis with concurrent tendovaginitis. Conventional x-ray studies of the hands and feet presented predominantly osteoarthritic lesions with possible indirect signs of arthritis. The mutation p.Glu313Lys in NLRP3-3 was detected in a moleculargenetic multi-gene panel by the audiogenetic out-patient department of UMG. Severe bilateral sensorineural hearing loss was confirmed by audiometry. A cranial MRI to further investigate the intermittently ocurring vertigo remained unremarkabale.

Therapy: Genetic testing revealed the above-mentioned mutation in NLRP-3, encoding a protein previously called cryopyrin which forms part of the interleukin 1-inflammosome regulating the production of interleukin-1 beta [1]. Thus, the diagnosis of Muckle-Wells Syndrome was established and a treatment with the anti-interleukin-1 beta antibody Canakinumab initiated (150 mg every two months). Muckle-Wells Syndrome belongs to the group of cryopyrin-associated periodic syndromes (CAPS) representing very rare disorders with an estimated prevalence of 1/360.000 and 135 cases of Muckle-Wells Syndrome reported worldwide [2]. The effectiveness of Canakinumab in CAPS has been demonstrated [3].

Further course: After initiation of therapy with the anti-interleukin-1 beta antibody Canakinumab the patient experienced rapid alleviation of symptoms. In follow-up consultations, episodic fever had ceded and arthralgias were absent. Levels of serum-amyloid A almost normalized (10.3 mg/l, ref. < 10 mg/l) Surprisingly, audiometric follow-up investigations did not reveal further decline of sensorineural hearing loss with remarkably good audiometric results and sufficient capacity of speech discrimination (with hearing aids) under the established therapy with Canakinumab. For this reason, an initially planned cochlea implant procedure was postponed indefinitely. Improved hearing levels under the therapy with anti-interleukin-1 beta antibody Canakinumab have been reported casuistically in Muckle-Wells Syndrome [4]. The remarkably late diagnosis of Muckle-Wells Syndrome in an elderly patient after genetic testing of her daughter and the favorable course of the patient, including audiometrically sustained hearing levels, under therapy with Canakinumab render the reported case exceptional. For clinical practice, sensorineural hearing loss, arthralgias, (urticarial) skin rashes, intermittent fever and relapsing conjunctivitis/uveitis -especially in younger patients- can prompt suspicion of underlying Muckle-Wells Syndrome.

Literatur

[1] Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol. 2008 Jan;4(1):34-42. DOI: 10.1038/ncprheum0681
[2] Orphanet. Available from: https://www.orpha.net/en
[3] Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Gitton X, Widmer A, Patel N, Hawkins PN; Canakinumab in CAPS Study Group. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009 Jun 4;360(23):2416-25. DOI: 10.1056/NEJMoa0810787
[4] Iida Y, Wakiguchi H, Okazaki F, Nakamura T, Yasudo H, Kubo M, Sugahara K, Yamashita H, Suehiro Y, Okayama N, Hashimoto K, Iwamoto N, Kawakami A, Aoki Y, Takada H, Ohga S, Hasegawa S. Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene. Clin Rheumatol. 2019 Mar;38(3):943-8. DOI: 10.1007/s10067-018-4331-8