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Cryopyrin-Associated Periodic Syndromes (CAPS)

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Textbook of Autoinflammation

Abstract

The cryopyrin-associated periodic syndromes (CAPS) include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) with shared and unique clinical features. Most patients possess heterozygous NLRP3 mutations leading to a hyperactive inflammasome, subsequent overproduction of interleukin (IL)-1β and inflammatory symptoms. Diagnostic challenges include a heterogeneous multi-systemic clinical presentation, somatic mosaicism, and low penetrance mutations. IL-1 targeted therapy has become the standard of care for CAPS based on its clinical efficacy and safety.

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Abbreviations

AIDAI:

Autoinflammatory Disease Activity Index

ASC:

Apoptosis-associated speck like protein containing a caspase recruitment domain

CAPS:

Cryopyrin-associated periodic syndromes

CARD:

Caspase activating and recruitment domain

CINCA:

Chronic infantile neurologic cutaneous and articular

CNS:

Central nervous system

CRP:

C-reactive protein

DAS:

Disease activity scale

ESR:

Erythrocyte sedimentation rate

FCAS:

Familial cold autoinflammatory syndrome

FMF:

Familial Mediterranean fever

IL:

Interleukin

LPS:

Lipopolysaccharide

LRR:

Leucine-rich repeat

MKD:

Mevalonate kinase deficiency

MWS:

Muckle-Wells syndrome

NLR:

NOD-like receptor

NLRP3:

Nucleotide binding and oligomerization domain, leucine rich repeat, pyrin 3

NOD:

Nucleotide-binding and oligomerization domain

NOMID:

Neonatal-onset multisystem inflammatory disease

NSAID:

Non-steroidal anti-inflammatory drug

PGE:

Prostaglandin E

PKA:

Protein kinase A

PYD:

Pyrin domain

SAA:

Serum amyloid A

TRAPS:

Tumor necrosis factor receptor-associated periodic syndrome

VAS:

Visual analog scale

References

  1. Aksentijevich I, Putnam CD, Remmers EF, 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.

    Article  CAS  Google Scholar 

  2. Neven B, Callebaut I, Prieur AM, 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.

    Article  CAS  Google Scholar 

  3. Kile RM, Rusk HA. A case of cold urticaria with an unusual family history. JAMA. 1940;114:1067–8.

    Google Scholar 

  4. Muckle TJ, Wells SM. Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Q J Med. 1962;31:235–48.

    CAS  Google Scholar 

  5. Prieur AM, Griscelli C. Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation. J Pediatr. 1981;99:79–83.

    Article  CAS  Google Scholar 

  6. Aksentijevich I, Nowak M, Mallah M, 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.

    Article  CAS  Google Scholar 

  7. Feldmann J, Prieur AM, Quartier P, 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. Saito M, Fujisawa A, Nishikomori R, et al. Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2005;52:3579–85.

    Article  CAS  Google Scholar 

  10. Tanaka N, Izawa K, Saito MK, et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum. 2011;63:3625–32.

    Article  CAS  Google Scholar 

  11. Zhou Q, Aksentijevich I, Wood GM, et al. Brief report: cryopyrin-associated periodic syndrome caused by a myeloid-restricted somatic NLRP3 mutation. Arthritis Rheumatol. 2015;67:2482–6.

    Article  CAS  Google Scholar 

  12. Kuemmerle-Deschner JB, Verma D, Endres T, et al. Clinical and molecular phenotypes of low-penetrance variants of NLRP3: diagnostic and therapeutic challenges. Arthritis Rheumatol. 2017;69:2233–40.

    Article  CAS  Google Scholar 

  13. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20:319–25.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. Wang L, Manji GA, Grenier JM, et al. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. J Biol Chem. 2002;277:29874–80.

    Article  CAS  Google Scholar 

  16. Tassi S, Carta S, Delfino L, 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.

    Article  CAS  Google Scholar 

  17. Rosengren S, Mueller JL, Anderson JP, et al. Monocytes from familial cold autoinflammatory syndrome patients are activated by mild hypothermia. J Allergy Clin Immunol. 2007;119:991–6.

    Article  CAS  Google Scholar 

  18. McGeough MD, Wree A, Inzaugarat ME, et al. TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies. J Clin Invest. 2017;127:4488–97.

    Article  Google Scholar 

  19. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355:581–92.

    Article  CAS  Google Scholar 

  20. Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med. 2003;348:2583–4.

    Article  Google Scholar 

  21. Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364:1779–85.

    Article  CAS  Google Scholar 

  22. Levy R, Gerard L, Kuemmerle-Deschner J, et al. Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis. 2015;74:2043–9.

    Article  CAS  Google Scholar 

  23. Yadlapati S, Efthimiou P. Impact of IL-1 inhibition on fatigue associated with autoinflammatory syndromes. Mod Rheumatol. 2016;26:3–8.

    Article  CAS  Google Scholar 

  24. Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol. 2001;108:615–20.

    Article  CAS  Google Scholar 

  25. Aubert P, Suarez-Farinas M, Mitsui H, et al. Homeostatic tissue responses in skin biopsies from NOMID patients with constitutive overproduction of IL-1beta. PLoS One. 2012;7:e49408.

    Article  CAS  Google Scholar 

  26. 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.

    Article  Google Scholar 

  27. Sibley CH, Plass N, Snow J, et al. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheum. 2012;64:2375–86.

    Article  CAS  Google Scholar 

  28. Almeida MQ, Tsang KM, Cheadle C, 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.

    Article  CAS  Google Scholar 

  29. Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481–9.

    Article  CAS  Google Scholar 

  30. Dollfus H, Hafner R, Hofmann HM, 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.

    Article  CAS  Google Scholar 

  31. Kawai M, Yoshikawa T, Nishikomori R, Heike T, Takahashi K. Obvious optic disc swelling in a patient with cryopyrin-associated periodic syndrome. Clin Ophthalmol. 2013;7:1581–5.

    PubMed  PubMed Central  Google Scholar 

  32. Ahmadi N, Brewer CC, Zalewski C, et al. Cryopyrin-associated periodic syndromes: otolaryngologic and audiologic manifestations. Otolaryngol Head Neck Surg. 2011;145:295–302.

    Article  Google Scholar 

  33. Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, et al. Hearing loss in Muckle-Wells syndrome. Arthritis Rheum. 2013;65:824–31.

    Article  CAS  Google Scholar 

  34. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360:2416–25.

    Article  CAS  Google Scholar 

  35. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004;50:607–12.

    Article  CAS  Google Scholar 

  36. Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361–71.

    Article  CAS  Google Scholar 

  37. Nirmala N, Grom A, Gram H. Biomarkers in systemic juvenile idiopathic arthritis: a comparison with biomarkers in cryopyrin-associated periodic syndromes. Curr Opin Rheumatol. 2014;26:543–52.

    Article  CAS  Google Scholar 

  38. Wittkowski H, Kuemmerle-Deschner JB, Austermann J, et al. MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes. Ann Rheum Dis. 2011;70:2075–81.

    Article  CAS  Google Scholar 

  39. Goldbach-Mansky R. Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep. 2011;13:123–31.

    Article  Google Scholar 

  40. Stych B, Dobrovolny D. Familial cold auto-inflammatory syndrome (FCAS): characterization of symptomatology and impact on patients’ lives. Curr Med Res Opin. 2008;24:1577–82.

    Article  Google Scholar 

  41. Fye KH, Siegel DH, Connolly MK. Diagnosis of Muckle-Wells syndrome—33 years later. J Rheumatol. 2007;34:2505–6.

    PubMed  Google Scholar 

  42. Piram M, Frenkel J, Gattorno M, 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. 2011;70:309–14.

    Article  Google Scholar 

  43. Cuisset LJI, Dumont B, Fabre A, et al for the French CAPS study group. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011;70:495–9.

    Article  Google Scholar 

  44. Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, et al. Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis. 2017;76:942–7.

    Article  Google Scholar 

  45. Hoffman HM, Throne ML, Amar NJ, 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.

    Article  CAS  Google Scholar 

  46. Sibley CH, Chioato A, Felix S, et al. A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease. Ann Rheum Dis. 2015;74:1714–9.

    Article  CAS  Google Scholar 

  47. Rodriguez-Smith J, Lin YC, Tsai WL, et al. 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 Rheumatol. 2017;69:1325–36.

    Article  CAS  Google Scholar 

  48. Goldbach-Mansky R. Blocking interleukin-1 in rheumatic diseases. Ann N Y Acad Sci. 2009;1182:111–23.

    Article  CAS  Google Scholar 

  49. Kuemmerle-Deschner JB, Wittkowski H, Tyrrell PN, et al. Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens. Arthritis Res Ther. 2013;15:R64.

    Article  CAS  Google Scholar 

  50. Neven B, Marvillet I, Terrada C, 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.

    Article  CAS  Google Scholar 

  51. Goldbach-Mansky R, Shroff SD, Wilson M, 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.

    Article  CAS  Google Scholar 

  52. Kuemmerle-Deschner JB, Hachulla E, Cartwright R, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2011;70:2095–102.

    Article  CAS  Google Scholar 

  53. LaRock CN, Todd J, LaRock DL, et al. IL-1beta is an innate immune sensor of microbial proteolysis. Sci Immunol. 2016;1:eaah3539.

    Article  Google Scholar 

  54. Jaeger VK, Hoffman HM, van der Poll T, et al. Safety of vaccinations in patients with cryopyrin-associated periodic syndromes: a prospective registry based study. Rheumatology (Oxford). 2017;56:1484–91.

    Article  CAS  Google Scholar 

  55. Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6:262.

    Article  Google Scholar 

  56. Aganna E, Martinon F, Hawkins PN, et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002;46:2445–52.

    Article  CAS  Google Scholar 

  57. Prieur AM, Griscelli C, Lampert F, 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.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Pediatric Allergy, Immunology, and Rheumatology, University of California at San Diego and Rady Children’s Hospital, San Diego, CA, USA

    Hal M. Hoffman

  2. Division of Paediatric Rheumatology, Department of Paediatrics and Autoinflammation Reference Center Tuebingen, University Hospital Tuebingen, Tuebingen, Germany

    Jasmin B. Kuemmerle-Deschner

  3. Translational Autoinflammatory Disease Section (TADS), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA

    Raphaela Goldbach-Mansky

Authors
  1. Hal M. Hoffman
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  2. Jasmin B. Kuemmerle-Deschner
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  3. Raphaela Goldbach-Mansky
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Corresponding author

Correspondence to Hal M. Hoffman .

Editor information

Editors and Affiliations

  1. Pediatric Rheumatology Unit, Shaare Zedek Medical Center and Hebrew University, Jerusalem, Israel

    Philip J. Hashkes

  2. Department Paediatrics, Division of Rheumatology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Ronald M. Laxer

  3. Department of Internal Medicine, Radboudumc Expertisecenter for Immunodeficiency and Autoinflammation, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna Simon

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Hoffman, H.M., Kuemmerle-Deschner, J.B., Goldbach-Mansky, R. (2019). Cryopyrin-Associated Periodic Syndromes (CAPS). In: Hashkes, P., Laxer, R., Simon, A. (eds) Textbook of Autoinflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-98605-0_19

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  • DOI: https://doi.org/10.1007/978-3-319-98605-0_19

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