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Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene

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Abstract

Cryopyrin-associated periodic syndrome (CAPS) is one of the autoinflammatory disorders caused by mutations in NLRP3 gene. The over-production of interleukin (IL)-1β induced by NLRP3 gene mutations plays an important role in the pathophysiology of CAPS. We diagnosed 3 patients with CAPS, who were lineal family members having a novel mutation of NLRP3 gene. The objective of this report is to compare the characteristics of symptoms and differences in the therapeutic responses of them, who had the same mutation. In addition, we aimed to examine the usefulness of cytokine measurement for diagnosis or determination of treatment effect of CAPS. A 5-year-old Japanese boy (proband) came to our hospital because of short stature, reached the diagnosis of Muckle-Wells syndrome (MWS) due to a mutation in NLRP3 gene, which had not been reported so far (p.G328E, c.G983A). His mother and grandmother harbored the same mutation of NLRP3. We measured serum concentrations of cytokines in the proband assessed by flow-cytometric bead array. All of them had episodic skin eruptions with conjunctivitis, hearing loss, and arthralgia, but not periodic fever, cold-triggered episodes, and chronic aseptic meningitis. Only the proband had short stature. Canakinumab therapy led to a prompt relief of symptoms and normalized laboratory data in all patients. Audiograms demonstrated an improved hearing level in the proband, but not two others despite of the same mutation. All cytokines did not show any characteristic findings. Sensorineural hearing loss and itchless rash but not serum cytokine profile deserved attention to the diagnosis and treatment start of CAPS. The early intervention of IL-1β blockade may reduce the chance of complete deafness in patients with CAPS.

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References

  1. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 29:301–305

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Kuemmerle-Deschner JB, Haug I (2013) Canakinumab in patients with cryopyrin-associated periodic syndrome: an update for clinicians. Ther Adv Musculoskelet Dis 5:315–329

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Aoyama K, Amano H, Takaoka Y, Nishikomori R, Ishikawa O (2012) Cryopyrin-associated periodic syndrome: a case report and review of the Japanese literature. Acta Derm Venereol 92:395–398

    Article  PubMed  Google Scholar 

  4. Ohnishi H, Teramoto T, Iwata H, Kato Z, Kimura T, Kubota K, Nishikomori R, Kaneko H, Seishima M, Kondo N (2012) Characterization of NLRP3 variants in Japanese cryopyrin-associated periodic syndrome patients. J Clin Immunol 32:221–229

    Article  PubMed  CAS  Google Scholar 

  5. Hoffman HM, Wanderer AA (2010) Inflammasome and IL-1beta-mediated disorders. Curr Allergy Asthma Rep 10:229–235

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Cuisset L, Jeru I, Dumont B, Fabre A, Cochet E, Le Bozec J, French CAPS Study Group et al (2011) Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis 70:495–499

    Article  PubMed  CAS  Google Scholar 

  7. Mehr S, Allen R, Boros C, Adib N, Kakakios A, Turner PJ, Rogers M, Zurynski Y, Singh-Grewal D (2016) Cryopyrin-associated periodic syndrome in Australian children and adults: epidemiological, clinical and treatment characteristics. J Paediatr Child Health 52:889–895

    Article  PubMed  Google Scholar 

  8. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Canakinumab in CAPS Study Group et al (2009) Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360:2416–2425

    Article  PubMed  CAS  Google Scholar 

  9. Yu JF, Leslie KS (2011) Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep 11:12–20

    Article  PubMed  CAS  Google Scholar 

  10. Schroder K, Zhou R, Tschopp J (2010) The NLRP3 inflammasome: a sensor for metabolic danger? Science 327:296–300

    Article  PubMed  CAS  Google Scholar 

  11. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J (2004) NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319–325

    Article  PubMed  CAS  Google Scholar 

  12. De Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P, Poli V et al (1997) Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest 99:643–650

    Article  PubMed  PubMed Central  Google Scholar 

  13. Levy R, Gérard L, Kuemmerle-Deschner J, Lachmann HJ, Koné-Paut I, Cantarini L, for PRINTO and Eurofever et al (2015) Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis 74:2043–2049

    Article  PubMed  CAS  Google Scholar 

  14. Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, Hansmann S, Plontke SK, Koitschev C, Koetter I, Angermair E, Benseler SM (2013) Hearing loss in Muckle-Wells syndrome. Arthritis Rheum 65:824–831

    Article  PubMed  CAS  Google Scholar 

  15. Kuemmerle-Deschner JB, Koitschev A, Tyrrell PN, Plontke SK, Deschner N, Hansmann S, Ummenhofer K, Lohse P, Koitschev C, Benseler SM (2015) Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. Pediatr Rheumatol Online J 13:43

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, Anderson JP, Wanderer AA, Firestein GS (2004) Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364:1779–1785

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, Pham TH, Pucino F, Wesley RA, Papadopoulos JH, Weinstein SP, Mellis SJ, Kastner DL (2008) A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum 58:2432–2442

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Rodriguez-Smith J, Lin YC, Tsai WL, Kim H, Montealegre-Sanchez G, Chapelle D et al (2017) Cerebrospinal fluid cytokines correlate with aseptic meningitis and blood-brain barrier function in neonatal-onset multisystem inflammatory disease: central nervous system biomarkers in neonatal-onset multisystem inflammatory disease correlate with central nervous system inflammation. Arthritis Rheum 69:1325–1336

    Article  CAS  Google Scholar 

  19. Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, Carta S, Tengesdal I, Nemkov T, D’Alessandro A, Henry C, Jones GS, Goodrich SA, St. Laurent JP, Jones TM, Scribner CL, Barrow RB, Altman RD, Skouras DB, Gattorno M, Grau V, Janciauskiene S, Rubartelli A, Joosten LAB, Dinarello CA (2018) OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A 115:E1530–E1539

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, Kone-Paut I, Goldbach-Mansky R, Lachmann H, Blank N, Hoffman HM, Weissbarth-Riedel E, Hugle B, Kallinich T, Gattorno M, Gul A, ter Haar N, Oswald M, Dedeoglu F, Cantarini L, Benseler SM (2017) Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis 76:942–947

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank the patients and their family for their cooperation.

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Authors and Affiliations

  1. Department of Pediatrics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan

    Yasunori Iida, Hiroyuki Wakiguchi, Fumiko Okazaki, Tamaki Nakamura, Hiroki Yasudo, Shouichi Ohga & Shunji Hasegawa

  2. Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan

    Makoto Kubo

  3. Department of Otolaryngology, Yamaguchi University Graduate School of Medicine, Ube, Japan

    Kazuma Sugahara & Hiroshi Yamashita

  4. Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan

    Yutaka Suehiro

  5. Division of Laboratory, Yamaguchi University Graduate School of Medicine, Ube, Japan

    Naoko Okayama

  6. Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Kunio Hashimoto

  7. Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Naoki Iwamoto & Atsushi Kawakami

  8. Division of Pediatrics, Nagato General Hospital, Nagato, Japan

    Yoshiharu Aoki

  9. Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Hidetoshi Takada

  10. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University Faculty of Medicine, Fukuoka, Japan

    Shouichi Ohga

Authors
  1. Yasunori Iida
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  2. Hiroyuki Wakiguchi
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  3. Fumiko Okazaki
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  4. Tamaki Nakamura
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  6. Makoto Kubo
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  7. Kazuma Sugahara
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  8. Hiroshi Yamashita
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  9. Yutaka Suehiro
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  10. Naoko Okayama
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  11. Kunio Hashimoto
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  12. Naoki Iwamoto
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  13. Atsushi Kawakami
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  14. Yoshiharu Aoki
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  15. Hidetoshi Takada
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  16. Shouichi Ohga
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  17. Shunji Hasegawa
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Corresponding author

Correspondence to Hiroyuki Wakiguchi.

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Electronic supplementary material

ESM 1

The results of genetic tests in the family with MWS. All the patients had a novel mutation in NLRP3 gene located on chromosome 1q44, p.G328E, c.G983A. (PNG 573 kb)

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Iida, Y., Wakiguchi, H., Okazaki, F. et al. Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene. Clin Rheumatol 38, 943–948 (2019). https://doi.org/10.1007/s10067-018-4331-8

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  • DOI: https://doi.org/10.1007/s10067-018-4331-8

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