Advertisement

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

  • Raphaela Goldbach-ManskyEmail author
Article

Abstract

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin- (NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1β overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the “NLRP3 inflammasome,” an intracellular platform that processes and secretes increased amounts of IL-1β. The pivotal role of IL-1β in NOMID/CINCA has been demonstrated in several clinical studies using IL-1—blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1—blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient’s disease severity and organ manifestations.

Keywords

IL-1 Autoinflammatory diseases NOMID CINCA NLRP3 CIAS1 CAPS IL-1Ra Anakinra Neonatal disorder Genetic disease 

Notes

Disclosure

Dr. Goldbach-Mansky has received grant support from Novartis and Regeneron Pharmaceuticals.

References

  1. 1.
    Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002;71:198–203.PubMedCrossRefGoogle Scholar
  2. 2.
    Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46:3340–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29:301–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Hoffman HM, Gregory SG, Mueller JL, Tresierras M, Broide DH, Wanderer AA, et al. Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P. Hum Genet. 2003;112:209–16.PubMedGoogle Scholar
  5. 5.
    Infevers: an online database for autoinflammatory mutations. Available at http://fmf.igh.cnrs.fr/ISSAID/infevers/index.php. Accessed January 2011.
  6. 6.
    Neven B, Callebaut I, Prieur AM, Feldmann J, Bodemer C, Lepore L, et al. Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood. 2004;103:2809–15.PubMedCrossRefGoogle Scholar
  7. 7.
    Aksentijevich I, Putnam D, Remmers EF, Mueller JL, Le J, Kolodner RD, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56:1273–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355:581–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Prieur AM, Griscelli C, Lampert F, Truckenbrodt H, Guggenheim MA, Lovell DJ, et al. A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatol Suppl. 1987;66:57–68.PubMedCrossRefGoogle Scholar
  10. 10.
    Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87:2095–147.PubMedGoogle Scholar
  11. 11.
    Muckle TJ. The ‘Muckle-Wells’ syndrome. Br J Dermatol. 1979;100:87–92.PubMedCrossRefGoogle Scholar
  12. 12.
    Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010;62:258–67.PubMedCrossRefGoogle Scholar
  13. 13.
    Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum. 2007;56:1706–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Dollfus H, Hafner R, Hofmann HM, Russo RA, Denda L, Gonzales LD, et al. Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease syndrome: ocular manifestations in a recently recognized chronic inflammatory disease of childhood. Arch Ophthalmol. 2000;118:1386–92.PubMedGoogle Scholar
  15. 15.
    Rigante D, Stabile A, Minnella A, Avallone L, Ziccardi L, Bersani G, et al. Post-inflammatory retinal dystrophy in CINCA syndrome. Rheumatol Int. 2010;30:389–93.PubMedCrossRefGoogle Scholar
  16. 16.
    Kitley JL, Lachmann HJ, Pinto A, Ginsberg L. Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology. 2010;74:1267–70.PubMedCrossRefGoogle Scholar
  17. 17.
    Hill SC, Namde M, Dwyer A, Poznanski A, Canna S, Goldbach-Mansky R. Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA). Pediatr Radiol. 2007;37:145–52.PubMedCrossRefGoogle Scholar
  18. 18.
    Torbiak RP, Dent PB, Cockshott WP. NOMID—a neonatal syndrome of multisystem inflammation. Skeletal Radiol. 1989;18:359–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Saito M, Fujisawa A, Nishikomori R, Kambe N, Nakata-Hizume M, Yoshimoto M, et al. Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2005;52:3579–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Saito M, Nishikomori R, Kambe N, Fujisawa A, Tanizaki H, Takeichi K, et al. Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Blood. 2008;111:2132–41.PubMedCrossRefGoogle Scholar
  21. 21.
    Arostegui JI, Lopez S, Pascal M, Clemente D, Aymerich M, Balaguer F, et al. A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic, cutaneous, articular syndrome/neonatal-onset multisystem inflammatory disease: novel evidence of the role of low-level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases. Arthritis Rheum. 2010;62:1158–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Goldbach-Mansky R, Plass N, Chapelle D, NOMID study group. Treatment of neonatal-onset multisystem inflammatory disease (NOMID/CINCA) with IL-1 blocker anakinra, after 3 years on treatment. Arthritis Rheum. 2008;58:S633.CrossRefGoogle Scholar
  23. 23.
    Almeida MQ, Tsang KM, Cheadle C, Watkins T, Grivel JC, Nesterova M, et al. Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between cyclic AMP and pro-inflammatory pathways in osteoblast progenitors. Hum Mol Genet. 2011;20:165–75.PubMedCrossRefGoogle Scholar
  24. 24.
    Ausubel FM. Are innate immune signaling pathways in plants and animals conserved? Nat Immunol. 2005;6:973–79.PubMedCrossRefGoogle Scholar
  25. 25.
    Ting JP, Duncan JA, Lei Y. How the noninflammasome NLRs function in the innate immune system. Science. 2010;327:286–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11:136–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Meissner F, Molawi K, Zychlinsky A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol. 2008;9:866–72.PubMedCrossRefGoogle Scholar
  29. 29.
    Tassi S, Carta S, Delfino L, Caorsi R, Martini A, Gattorno M, et al. Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1beta secretion. Proc Natl Acad Sci U S A. 2010;107:9789–94.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2010 Dec 1 (Epub ahead of print).Google Scholar
  31. 31.
    Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360:2426–37.PubMedCrossRefGoogle Scholar
  32. 32.
    Yazdi AS, Drexler SK, Tschopp J. The role of the inflammasome in nonmyeloid cells. J Clin Immunol. 2010;30:623–27.PubMedCrossRefGoogle Scholar
  33. 33.
    Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A, Gandhi C, et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009;30:875–87.PubMedCrossRefGoogle Scholar
  34. 34.
    Meng G, Zhang F, Fuss I, Kitani A, Strober W. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity. 2009;30:860–74.PubMedCrossRefGoogle Scholar
  35. 35.
    Borth W, Urbanski A, Prohaska R, Susanj M, Luger TA. Binding of recombinant interleukin-1 beta to the third complement component and alpha 2-macroglobulin after activation of serum by immune complexes. Blood. 1990;75:2388–95.PubMedGoogle Scholar
  36. 36.
    Lachmann HJ, Lowe P, Felix SD, Rordorf C, Leslie K, Madhoo S, et al. In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes. J Exp Med. 2009;206:1029–36.PubMedCrossRefGoogle Scholar
  37. 37.
    Fox E, Jayaprakash N, Pham TH, Rowley A, McCully CL, Pucino F, et al. The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates. J Neuroimmunol. 2010;223:138–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364:1779–85.PubMedCrossRefGoogle Scholar
  39. 39.
    Caroli F, Pontillo A, D’Osualdo A, Travan L, Ceccherini I, Crovella S, et al. Clinical and genetic characterization of Italian patients affected by CINCA syndrome. Rheumatology (Oxford). 2007;46:473–78.CrossRefGoogle Scholar
  40. 40.
    Ross JB, Finlayson LA, Klotz PJ, Langley RG, Gaudet R, Thompson K, et al. Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up. J Cutan Med Surg. 2008;12:8–16.PubMedGoogle Scholar
  41. 41.
    Lepore L, Paloni G, Caorsi R, Alessio M, Rigante D, Ruperto N, et al. Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with Anakinra. J Pediatr. 2010;157:310–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58:2443–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, et al. 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. 2008;58:2432–42.PubMedCrossRefGoogle Scholar
  44. 44.
    Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360:2416–25.PubMedCrossRefGoogle Scholar
  45. 45.
    Anakinra package insert. Available at http://www.kineretrx.com/professional/pi.jsp.
  46. 46.
    Rilonacept package insert. Available at http://www.regeneron.com/ARCALYST-fpi.pdf.
  47. 47.
    Canakinumab package insert. Available at http://www.pharma.us.novartis.com/products/name/ilaris.jsp.
  48. 48.
    Piram M, Frenkel J, Gattorno M, Ozen S, Lachmann HJ, Goldbach-Mansky R et al. A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Ann Rheum Dis. 2010.Google Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2011

Authors and Affiliations

  1. 1.Translational Autoinflammatory Disease SectionNational Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of HealthBethesdaUSA

Personalised recommendations