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Cryopyrin-assoziiertes periodisches Syndrom

Cryopyrin-associated periodic syndrome

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Zusammenfassung

Das Cryopyrin-assoziierte periodische Syndrom (CAPS) ist eine äußerst seltene Erkrankung. Schätzungen gehen von 1 bis 2 Fällen auf 1 Mio. Menschen in den USA und 1/360.000 in Frankreich aus. Da viele Patienten nicht oder nur sehr spät diagnostiziert werden, dürfte die tatsächliche Prävalenz höher liegen. CAPS umfasst die 3 Entitäten FCAS („familial cold autoinflammatory syndrome“), das Muckle-Wells-Syndrom (MWS) und das NOMID („neonatal-onset multisystem inflammatory disease“)/CINCA („chronic infantile neurologic, cutaneous and articular“)-Syndrom. Gemeinsam ist diesen Erkrankungen eine ursächliche Mutation im NRLP3-Gen. Das veränderte Genprodukt Cryopyrin führt zur Aktivierung des Inflammasoms mit exzessiver Ausschüttung von IL-1β. IL-1β ist für die inflammatorischen Manifestationen von CAPS verantwortlich. Diese äußern sich als systemische und lokale Entzündung mit Fieber, Kopfschmerz, Fatigue, Hautausschlag, Augenbeteiligung, progressiver Hörminderung, muskuloskelettalen Beschwerden und ZNS-Manifestation (nur NOMID/CINCA). Mit den IL-1-Inhibitoren Anakinra, Rilonacept und Canakinumab stehen erstmals effektive und sichere Therapieoptionen für diese stark beeinträchtigende Erkrankung zur Verfügung. Um schwere und zum Teil lebensbedrohliche Krankheitsfolgen zu verhindern, sind eine frühe korrekte Diagnose und ein möglichst frühzeitiger Therapiebeginn unerlässlich.

Abstract

The cryopyrin-associated periodic syndrome is a very rare disease. It is estimated that there are 1–2 cases out of 1 million inhabitants in the USA and 1/360,000 in France. However, many patients are diagnosed very late or not at all. Therefore the real prevalence is likely to be higher. CAPS encompasses the three entities familial cold autoinflammatory syndrome (FCAS), the Muckle-Wells syndrome and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3-gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of IL-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and CNS symptoms (NOMID/CINCA only). With the advent of the IL-1 inhibitors anakinra, rilonacept and canakinumab for the first time safe and effective therapeutic options are available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory.

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Abbreviations

AID:

autoinflammatory disease

BSG:

Blutkörperchensenkungsgeschwindigkeit

CAPS:

Cryopyrin-assoziiertes periodisches Syndrom

CIAS:

cold induced autoinflammatory syndrome

CINCA:

chronic infantile neurological cutaneous and articular syndrome

COX 2:

cyclooxygenase type 2

CRP:

C-reaktives Protein

dB:

Dezibel

FACIT:

functional assessment of chronic illness therapy

FCAS:

familial cold autoinflammatory syndrome

FLAIR:

fluid attenuated inversion recovery

HAQ:

Health Assessment Questionnaire

Ig G1:

Immunglobulin G1

IL-1β:

Interleukin-1β

IL-1R:

Interleukin-1-Rezeptor

IL-1Ra:

Interleukin-1-Rezeptorantagonist

IL-1RAcP:

Interleukin-1 Rezeptor-Adapterprotein

iNOS:

inducible nitric oxide synthetase

IQ:

Intelligenzquotient

kHz:

Kilohertz

MRP 8/14:

myeloid-related protein 8/14

MRT:

Magnetresonanztomographie

MTX:

Methotrexat

MWS:

Muckle-Wells-Syndrom

MWS-DAS:

Muckle-Wells Syndrome Disease Activity Score

NACHT:

NAIP, CIITA, HET-E, TP1

NALP:

NACHT, leucine-rich-repeat and pyrin domains containing protein

NLR:

nod-like-receptor

NLRP:

nucleotide-binding oligomerization domain, leucine-rich-repeat-family, pyrin domain containing protein

NOD:

nucleotide-binding oligomerization domain

NOMID:

neonatal-onset multisystem inflammatory disease

NSAID:

non-steroidal anti-inflammatory drugs

PedsQL:

Pediatric Quality of Life Inventory

PGE2:

Prostaglandin E2

SAA:

Serum Amyloid A

TLR:

toll-like-receptor

TNF-α:

Tumornekrosefaktor-α

VAS:

visuelle Analogskala

ZNS:

zentrales Nervensystem

Literatur

  1. Aganna E, Martinon F, Hawkins PN 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):2445–2452

    Article  PubMed  CAS  Google Scholar 

  2. Ahmadi N, Brewer CC, Zalewski C et al (2011) Cryopyrin-associated periodic syndromes: otolaryngologic and audiologic manifestations. Otolaryngol Head Neck Surg 145(2):295–302

    Article  PubMed  Google Scholar 

  3. Aksentijevich I, Nowak M, Mallah M 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):3340–3348

    Article  PubMed  CAS  Google Scholar 

  4. Aksentijevich I, D Putnam C, Remmers EF et al (2007) The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum 56(4):1273–1285

    Article  PubMed  CAS  Google Scholar 

  5. Aksentijevich I, Masters SL, Ferguson PJ et al (2009) An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 360(23):2426–2437

    Article  PubMed  CAS  Google Scholar 

  6. Cuisset L, Jeru I, Dumont B 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(3):495–499

    Article  PubMed  CAS  Google Scholar 

  7. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550

    Article  PubMed  CAS  Google Scholar 

  8. Dollfus H, Häfner R, Hofmann HM 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):1386–1392

    PubMed  CAS  Google Scholar 

  9. Farasat S, Aksentijevich I, Toro JR (2008) Autoinflammatory diseases: clinical and genetic advances. Arch Dermatol 144(3):392–402

    Article  PubMed  CAS  Google Scholar 

  10. Feldmann J, Prieur AM, Quartier P et al (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):198–203

    Article  PubMed  CAS  Google Scholar 

  11. 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):28–37

    Article  PubMed  CAS  Google Scholar 

  12. Fye KH, Siegel DH, Connolly MK (2007) Diagnosis of Muckle-Wells syndrome – 33 years later. J Rheumatol 34(12):2505–2506

    PubMed  Google Scholar 

  13. Gabay C (2003) IL-1 trap. Regeneron/Novartis. Curr Opin Investig Drugs 4(5):593–597

    PubMed  CAS  Google Scholar 

  14. Glaser RL, Goldbach-Mansky R (2008) The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies. Curr Allergy Asthma Rep 8(4):288–298

    Article  PubMed  CAS  Google Scholar 

  15. Goldbach-Mansky R, Dailey NJ, Canna SW et al (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355(6):581–592

    Article  PubMed  CAS  Google Scholar 

  16. Goldbach-Mansky R (2011) Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep 13(2):123–131

    Article  PubMed  Google Scholar 

  17. Hawkins PN, Lachmann HJ, McDermott MF (2003) Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med 348(25):2583–2584

    Article  PubMed  Google Scholar 

  18. Hill SC, Namde M, Dwyer A et al (2007) Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA). Pediatr Radiol 37(2):145–152

    Article  PubMed  Google Scholar 

  19. Hoffman HM, Mueller JL, Broide DH et al (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):301–305

    Article  PubMed  CAS  Google Scholar 

  20. Hoffman HM, Throne ML, Amar NJ et al (2008) Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 58(8):2443–2452

    Article  PubMed  CAS  Google Scholar 

  21. Infevers: The registry of hereditary auto-inflammatory disorders mutations. http://fmf.igh.cnrs.fr/ISSAID/infevers/ (zuletzt überprüft 03/2012)

  22. Kastner DL (2005) Hereditary periodic fever syndromes. Hematology Am Soc Hematol Educ Program. 74–81

  23. Kitley JL, Lachmann HJ, Pinto A, Ginsberg L (2010) Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology 74(16):1267–1270

    Article  PubMed  CAS  Google Scholar 

  24. Kone-Paut I, Lachmann HJ, Kuemmerle-Deschner JB et al (2011) Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study. Arthritis Res Ther 13(6):R202

    Article  PubMed  CAS  Google Scholar 

  25. Kümmerle-Deschner JB, Tyrrell PN, Reess F et al (2010) Risk factors for severe Muckle-Wells syndrome. Arthritis Rheum 62(12):3783–3791

    Article  PubMed  Google Scholar 

  26. Kuemmerle-Deschner JB, Tyrrell PN, Koetter I et al (2011) Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum 63(3):840–849

    Article  PubMed  Google Scholar 

  27. Kuemmerle-Deschner JB, Hachulla E, Cartwright R et al (2011) 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 70(12):2095–2102

    Article  PubMed  CAS  Google Scholar 

  28. Kuemmerle-Deschner JB, Lohse P, Koetter I et al (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):R196

    Article  PubMed  CAS  Google Scholar 

  29. Lachmann HJ, Goodman HJ, Gilbertson JA et al (2007) Natural history and outcome in systemic AA amyloidosis. N Engl J Med 356(23):2361–2371

    Article  PubMed  CAS  Google Scholar 

  30. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB et al (2009) Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360(23):2416–2425

    Article  PubMed  CAS  Google Scholar 

  31. Lainka E, Bielak M, Hilger V et al (2011) Translational research network and patient registry for auto-inflammatory diseases. Rheumatology (Oxford) 50(1):237–242

    Google Scholar 

  32. Lepore L, Paloni G, Caorsi R et al (2010) Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with anakinra. J Pediatr 157(2):310–315

    Article  PubMed  Google Scholar 

  33. Neven B, Marvillet I, Terrada C et al (2010) 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 62(1):258–267

    Article  PubMed  CAS  Google Scholar 

  34. Petrilli V, Dostert C, Muruve DA, Tschopp J (2007) The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol 19(6):615–622

    Article  PubMed  CAS  Google Scholar 

  35. Saito M, Nishikomori R, Kambe N et al (2008) Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Blood 111(4):2132–2141

    Article  PubMed  CAS  Google Scholar 

  36. 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):1577–1582

    Article  PubMed  Google Scholar 

  37. Tanaka N, Izawa K, Saito MK 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):3625–3632

    Article  PubMed  CAS  Google Scholar 

  38. Toplak N, Frenkel J, Ozen S (2012) An international registry on autoinflammatory diseases: the Eurofever experience. Ann Rheum Dis [Epub ahead of print]

  39. Touitou I, Koné-Paut I (2008) Autoinflammatory diseases. Best Pract Res Clin Rheumatol 22(5):811–829

    Article  PubMed  CAS  Google Scholar 

  40. Wittkowski H, Kuemmerle-Deschner JB, Austermann J 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):2075–2081

    Article  PubMed  CAS  Google Scholar 

  41. Ye Z, Ting JP (2008) NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr Opin Immunol 20(1):3–9

    Article  PubMed  CAS  Google Scholar 

  42. Dinarello CA (2005) Blocking IL-1 in systemic inflammation. J Exp Med 201(9):1355–1359

    Article  PubMed  CAS  Google Scholar 

  43. Kümmerle-Deschner J (2011) Cryopyrin-assoziierte periodische Syndrome (CAPS), 1. Aufl. UNI-MED, Bremen

  44. Church LD, Cook GP, McDermott MF (2008) Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol 4(1):34–42

    Article  PubMed  CAS  Google Scholar 

  45. Alten R, Gram H, Joosten LA et al (2008) The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 10(3):R67

    Article  PubMed  Google Scholar 

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: Dr. Jasmin Kümmerle-Deschner erhielt Honorar für Vorträge, Reisekostenübernahme für Kongresse und Unterstützung für die Durchführung klinischer Studien von Novartis Pharma AG.

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  1. Klinik für Kinder- und Jugendmedizin, Abteilung für pädiatrische Rheumatologie, Autoinflammation Reference Center Tübingen, Universitätsklinikum Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Deutschland

    J.B. Kümmerle-Deschner

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Kümmerle-Deschner, J. Cryopyrin-assoziiertes periodisches Syndrom. Z. Rheumatol. 71, 199–208 (2012). https://doi.org/10.1007/s00393-011-0856-9

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