Advertisement

Seminars in Immunopathology

, Volume 37, Issue 4, pp 377–385 | Cite as

CAPS — pathogenesis, presentation and treatment of an autoinflammatory disease

  • Jasmin B. Kuemmerle-Deschner
Review

Abstract

The cryopyrin-associated periodic syndrome (CAPS) is a severity spectrum of rare diseases. CAPS comprises the three conditions previously described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome. The clinical phenotype of CAPS is characterized by systemic inflammation. General symptoms are fatigue and fever. Local manifestations affect multiple tissues such as skin, joints, muscles, eyes, and the central nervous system. Distinct clinical features are characteristic for each subphenotype. In FCAS, these are cold-induced urticaria and fever, in MWS systemic amyloidosis and hearing loss and in NOMID/CINCA central nervous system inflammation and bone deformities. CAPS is caused by single heterozygous germline or somatic gain of function mutations in the NLRP3 gene encoding the protein cryopyrin. Cryopyrin nucleates an NLRP3 inflammasome, which regulates the activation and cleavage of caspase-1 that cleaves the pro-inflammatory cytokines, IL-1β and IL-18. IL-1β plays the key role in the induction of inflammation in CAPS. This has been confirmed by the application of IL-1 blocking agents, which lead not only to a rapid and sustained reversal of daily symptoms but also to some extent of long-term disease sequelae. To prevent CAPS-induced organ damage, early diagnosis and swift initiation of effective treatment are mandatory.

Keywords

Cryopyrin-associated periodic syndrome Autoinflammation IL-1 inhibition Mutation 

Notes

Conflict of interest statement

Dr. Kuemmerle-Deschner is consultant/speaker for Novartis and Sobi pharmaceuticals. She has received grant support from Sobi and Novartis.

References

  1. 1.
    Hoffman HM, Wanderer AA, Broide DH (2001) Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 108(4):615–620PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    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(3):301–305PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P et al (2002) 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 46(12):3340–3348PubMedCrossRefGoogle Scholar
  4. 4.
    Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint BG (2002) 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 71(1):198–203PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, Lesage S, Waterham H, Wise C, Sarrauste de Menthiere C et al (2008) The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 29(6):803–808PubMedCrossRefGoogle Scholar
  6. 6.
    Infevers: the registry of hereditary auto-inflammatory disorders mutations. http://fmfighcnrsfr/ISSAID/infevers, last Accessed March 2013
  7. 7.
    Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, Kolodner RD, Moak Z, Chuang M, Austin F, Goldbach-Mansky R et al (2007) The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum 56(4):1273–1285PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Kuemmerle-Deschner JB, Lohse P, Koetter I, Dannecker GE, Reess F, Ummenhofer K, Koch S, Tzaribachev N, Bialkowski A, Benseler SM (2011) NLRP3 E311K mutation in a large family with Muckle-Wells syndrome - description of a heterogeneous phenotype and response to treatment. Arthritis Res Ther 13(6):R196PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Levy R, Gerard L, Kuemmerle-Deschner J, Lachmann HJ, Kone-Paut I, Cantarini L, Woo P, Naselli A, Bader-Meunier B, Insalaco A et al (2014) Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum DisGoogle Scholar
  10. 10.
    Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, Nishikomori R, Morimoto T, Kambe N, Goldbach-Mansky R et al (2011) High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum 63(11):3625–3632PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, Lachmann HJ, Bybee A, Gaudet R, Woo P et al (2002) 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 46(9):2445–2452PubMedCrossRefGoogle Scholar
  12. 12.
    Kone-Paut I, Darce-Bello M, Shahram F, Gattorno M, Cimaz R, Ozen S, Cantarini L, Tugal-Tutktun I, Assaad-Khalil S, Hofer M et al (2011) Registries in rheumatological and musculoskeletal conditions. Paediatric Behcet’s disease: an international cohort study of 110 patients. One-year follow-up data. Rheumatology (Oxford) 50(1):184–188CrossRefGoogle Scholar
  13. 13.
    Rieber N, Gavrilov A, Hofer L, Singh A, Oz H, Endres T, Schafer I, Handgretinger R, Hartl D, Kuemmerle-Deschner J (2015) A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants. Clin Immunol 157(1):56–64PubMedCrossRefGoogle Scholar
  14. 14.
    Ye Z, Ting JP (2008) NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr Opin Immunol 20(1):3–9PubMedCrossRefGoogle Scholar
  15. 15.
    Petrilli V, Dostert C, Muruve DA, Tschopp J (2007) The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol 19(6):615–622PubMedCrossRefGoogle Scholar
  16. 16.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedCrossRefGoogle Scholar
  17. 17.
    Doherty TA, Brydges SD, Hoffman HM (2011) Autoinflammation: translating mechanism to therapy. J Leukoc Biol 90(1):37–47PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426PubMedCrossRefGoogle Scholar
  19. 19.
    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(3):319–325PubMedCrossRefGoogle Scholar
  20. 20.
    Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265PubMedCrossRefGoogle Scholar
  21. 21.
    Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9(8):847–856PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9(8):857–865PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Jiang Y, Wang M, Huang K, Zhang Z, Shao N, Zhang Y, Wang W, Wang S (2012) Oxidized low-density lipoprotein induces secretion of interleukin-1beta by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem Biophys Res Commun 425(2):121–126PubMedCrossRefGoogle Scholar
  24. 24.
    Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357–1361PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA et al (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183(2):787–791PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Franchi L, Eigenbrod T, Nunez G (2009) Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol 183(2):792–796PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Segovia J, Sabbah A, Mgbemena V, Tsai SY, Chang TH, Berton MT, Morris IR, Allen IC, Ting JP, Bose S (2012) TLR2/MyD88/NF-kappaB pathway, reactive oxygen species, potassium efflux activates NLRP3/ASC inflammasome during respiratory syncytial virus infection. PLoS One 7(1):e29695PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Ito S, Hara Y, Kubota T (2014) CARD8 is a negative regulator for NLRP3 inflammasome, but mutant NLRP3 in cryopyrin-associated periodic syndromes escapes the restriction. Arthritis Res Ther 16(1):R52PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Goldbach-Mansky R, Kastner DL (2009) Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol 124(6):1141–1149, quiz 1150–1141 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Ozkurede VU, Franchi L (2012) Immunology in clinic review series; focus on autoinflammatory diseases: role of inflammasomes in autoinflammatory syndromes. Clin Exp Immunol 167(3):382–390PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Balavoine JF, de Rochemonteix B, Williamson K, Seckinger P, Cruchaud A, Dayer JM (1986) Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). J Clin Invest 78(4):1120–1124PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343(6256):336–340PubMedCrossRefGoogle Scholar
  33. 33.
    Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550PubMedCrossRefGoogle Scholar
  34. 34.
    Hawkins PN, Lachmann HJ, McDermott MF (2003) Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med 348(25):2583–2584PubMedCrossRefGoogle Scholar
  35. 35.
    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(9447):1779–1785PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E et al (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355(6):581–592PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Farasat S, Aksentijevich I, Toro JR (2008) Autoinflammatory diseases: clinical and genetic advances. Arch Dermatol 144(3):392–402PubMedCrossRefGoogle Scholar
  38. 38.
    Cuisset L, Jeru I, Dumont B, Fabre A, Cochet E, Le Bozec J, Delpech M, Amselem S, Touitou I (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(3):495–499PubMedCrossRefGoogle Scholar
  39. 39.
    Stych B, Dobrovolny D (2008) Familial cold auto-inflammatory syndrome (FCAS): characterization of symptomatology and impact on patients’ lives. Curr Med Res Opin 24(6):1577–1582PubMedCrossRefGoogle Scholar
  40. 40.
    Toplak I, Rihtaric D, Hostnik P, Grom J, Stukelj M, Valencak Z (2012) Identification of a genetically diverse sequence of porcine reproductive and respiratory syndrome virus in Slovenia and the impact on the sensitivity of four molecular tests. J Virol Methods 179(1):51–56PubMedCrossRefGoogle Scholar
  41. 41.
    Fye KH, Siegel DH, Connolly MK (2007) Diagnosis of Muckle-Wells syndrome - 33 years later. J Rheumatol 34(12):2505–2506PubMedGoogle Scholar
  42. 42.
    Goldbach-Mansky R (2011) Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep 13(2):123–131PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Nakagawa K, Gonzalez-Roca E, Souto A, Kawai T, Umebayashi H, Campistol JM, Canellas J, Takei S, Kobayashi N, Callejas-Rubio JL et al (2015) Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. Ann Rheum Dis 74(3):603–610PubMedCrossRefGoogle Scholar
  44. 44.
    Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, Nishikomori R, Morimoto T, Kambe N, Goldbach-Mansky R et al (2011) High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum 63(11):3625–3632PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Kastner DL (2005) Hereditary periodic fever syndromes. Hematol Am Soc Hematol Educ Program 2005:74–81CrossRefGoogle Scholar
  46. 46.
    Dollfus H, Hafner R, Hofmann HM, Russo RA, Denda L, Gonzales LD, DeCunto C, Premoli J, Melo-Gomez J, Jorge JP et al (2000) 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 118(10):1386–1392PubMedCrossRefGoogle Scholar
  47. 47.
    Alejandre N, Ruiz-Palacios A, Garcia-Aparicio AM, Blanco-Kelly F, Bermudez S, Fernandez-Sanz G, Romero FI, Arostegui JI, Ayuso C, Jimenez-Alfaro I et al (2014) Description of a new family with cryopyrin-associated periodic syndrome: risk of visual loss in patients bearing the R260W mutation. Rheumatology (Oxford) 53(6):1095–1099CrossRefGoogle Scholar
  48. 48.
    Kawai M, Yoshikawa T, Nishikomori R, Heike T, Takahashi K (2013) Obvious optic disc swelling in a patient with cryopyrin-associated periodic syndrome. Clin Ophthalmol 7:1581–1585PubMedCentralPubMedGoogle Scholar
  49. 49.
    Ahmadi N, Brewer CC, Zalewski C, King KA, Butman JA, Plass N, Henderson C, Goldbach-Mansky R, Kim HJ (2011) Cryopyrin-associated periodic syndromes: otolaryngologic and audiologic manifestations. Otolaryngol–Head Neck Surg Off J Am Acad Otolaryngol-Head Neck Surg 145(2):295–302CrossRefGoogle Scholar
  50. 50.
    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(3):824–831PubMedCrossRefGoogle Scholar
  51. 51.
    Hill SC, Namde M, Dwyer A, Poznanski A, Canna S, Goldbach-Mansky R (2007) Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA). Pediatr Radiol 37(2):145–152PubMedCrossRefGoogle Scholar
  52. 52.
    Dode C, Cuisset L, Delpech M, Grateau G (2003) TNFRSF1A-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS) and renal amyloidosis. J Nephrol 16(3):435–437PubMedGoogle Scholar
  53. 53.
    Hashkes PJ, Lovell DJ (1997) Recognition of infantile-onset multisystem inflammatory disease as a unique entity. J Pediatr 130(4):513–515PubMedGoogle Scholar
  54. 54.
    Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, Hawkins PN (2007) Natural history and outcome in systemic AA amyloidosis. N Engl J Med 356(23):2361–2371PubMedCrossRefGoogle Scholar
  55. 55.
    Foell D, Wittkowski H, Vogl T, Roth J (2007) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81(1):28–37PubMedCrossRefGoogle Scholar
  56. 56.
    Wittkowski H, Kuemmerle-Deschner JB, Austermann J, Holzinger D, Goldbach-Mansky R, Gramlich K, Lohse P, Jung T, Roth J, Benseler SM et al (2011) MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes. Ann Rheum Dis 70(12):2075–2081PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Nirmala N, Grom A, Gram H (2014) Biomarkers in systemic juvenile idiopathic arthritis: a comparison with biomarkers in cryopyrin-associated periodic syndromes. Curr Opin Rheumatol 26(5):543–552PubMedCrossRefGoogle Scholar
  58. 58.
    Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, Zalewski C, Kim HJ, Bishop R, Hill S et al (2012) 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 64(7):2375–2386PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Gitton X, Widmer A, Patel N, Hawkins PN (2009) Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360(23):2416–2425PubMedCrossRefGoogle Scholar
  60. 60.
    Hoffman HM (2009) Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS). Expert Opin Biol Ther 9(4):519–531PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Division of Pediatric Rheumatology, Department of PediatricsUniversity Children’s Hospital TuebingenTuebingenGermany

Personalised recommendations