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Zeitschrift für Rheumatologie

, Volume 76, Issue 4, pp 322–327 | Cite as

Familiärer Chilblain-Lupus

Typ-I-Interferonopathie mit Modellcharakter
Leitthema

Zusammenfassung

Der familiäre Chilblain-Lupus ist eine Erkrankung aus der Gruppe der Typ-I-Interferonopathien und manifestiert sich v. a. durch charakteristische Hautveränderungen und Durchblutungsstörungen der Akren. Es gibt verschiedene Mutationen, die zu dieser autosomal-dominanten Erkrankung führen können. Am häufigsten wurde eine Mutation des Genes für TREX-1 beschrieben, aber auch Familien mit einer Mutation im SAMHD1-Gen und mit dem Gen des „proteins stimulator of interferon genes“ wurden entdeckt. Gemeinsam ist diesen genetischen Defekten, dass sie in den Prozess der Erkennung von intrazellulärer freier DNA involviert sind und im Resultat zu einer vermehrten Produktion von Typ-I-Interferonen und der dadurch induzierten Genprodukte führen. Dies wiederum führt zu Autoinflammation und Autoimmunität, die diese Erkrankung charakterisieren. Die Aktivierung der Interferon-induzierten Gene steht unter der Kontrolle des JAK/STAT-Systems. JAK-Inhibitoren wurden daher mehrfach erfolgreich in der Behandlung von Typ-I-Interferonopathien eingesetzt. Die Erfahrungen mit diesen neuen Therapien wachsen stetig.

Schlüsselwörter

JAK-Inhibitoren Mutation Autosomal-dominant Autoinflammation Autoimmunität 

Familial chilblain lupus

Type 1 interferonopathy with model character

Abstract

Familial chilblain lupus belongs to the group of type 1 interferonopathies and is particularly characterized by typical skin manifestations and ischemia of the acra. There are various mutations that can lead to this autosomal dominant disease. A mutation in the TREX-1 gene has been most frequently found; however, families with mutations in the SAMHD1 gene and recently in the gene which codes for the stimulator of interferon genes (STING) protein were also described. A common feature of these genetic defects is that they are all involved in the process of detection of intracellular free DNA, which as a result leads to increased production of type 1 interferons and the induced gene products. This then leads to autoinflammation and autoimmunity, which is characteristic for the disease. The activation of interferon-induced genes is controlled by the JAK-STAT system; therefore, JAK inhibitors were successfully used in several cases to treat type 1 interferonopathies. Experience with this treatment modality is continuously growing.

Keywords

JAK inhibitors Mutation Autosomal dominant Autoinflammation Autoimmunity 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

C. Fiehn gibt an, dass er Vortragshonorare von Pfizer erhält.

Dieser Beitrag beinhaltet keine vom Autor durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Crow YJ (2011) Type I interferonopathies: A novel set of inborn errors of immunity. Ann N Y Acad Sci 1238:91–98CrossRefPubMedGoogle Scholar
  2. 2.
    Rodero MP, Crow YJ (2016) Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med 213:2527–2538CrossRefPubMedGoogle Scholar
  3. 3.
    Lee-Kirsch MA, Wolf C, Kretschmer S et al (2015) Type I interferonopathies: An expanding disease spectrum of immunodysregulation. Semin Immunopathol 37:349–357CrossRefPubMedGoogle Scholar
  4. 4.
    König N, Fiehn C, Wolf C et al (2016) Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis 76(2):468–472CrossRefPubMedGoogle Scholar
  5. 5.
    Padeh S, Gerstein M, Greenberger S, Berkun Y (2013) Chronic chilblains: The clinical presentation and disease course in a large paediatric series. Clin Exp Rheumatol 31:463–468PubMedGoogle Scholar
  6. 6.
    Liu Y, Jesus AA, Marrero B et al (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Picard C, Thouvenin G, Kannengiesser C, Dubus JC, Jeremiah N, Rieux-Laucat F, Crestani B, Belot A, Thivolet-Béjui F, Secq V, Ménard C, Reynaud-Gaubert M, Reix P (2016) Severe pulmonary fibrosis as the first manifestation of interferonopathy (TMEM173 Mutation). Chest 150:e65–e71CrossRefPubMedGoogle Scholar
  8. 8.
    Gray EE, Treuting PM, Woodward JJ, Stetson DB (2015) Cutting Edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutières syndrome. J Immunol 195:1939–1943CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lee-Kirsch MA, Gong M, Schulz H, Rüschendorf F, Stein A, Pfeiffer C, Ballarini A, Gahr M, Hubner N, Linné M (2006) Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet 79:731–737CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, Robins P, Harvey S, Hollis T, O’Hara A, Herrick AL, Bowden AP, Perrino FW, Lindahl T, Barnes DE, Crow YJ (2007) Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet 80:811–815CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Günther C, Berndt N, Wolf C, Lee-Kirsch MA (2015) Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3’ repair exonuclease 1 (TREX1). JAMA Dermatol 151:426–431CrossRefPubMedGoogle Scholar
  12. 12.
    Günther C, Hillebrand M, Brunk J, Lee-Kirsch MA (2013) Systemic involvement in TREX1-associated familial chilblain lupus. J Am Acad Dermatol 69:e179–e181CrossRefPubMedGoogle Scholar
  13. 13.
    Aicardi J, Goutieres F (1984) A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15:49–54CrossRefPubMedGoogle Scholar
  14. 14.
    Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K, Hunger S, Borozdin W, Mah JK, Ungerath K, Walkenhorst H, Richardt HH, Buckard J, Bevot A, Siegel C, von Stülpnagel C, Ikonomidou C, Thomas K, Proud V, Niemann F, Wieczorek D, Häusler M, Niggemann P, Baltaci V, Conrad K, Lebon P, Lee-Kirsch MA (2010) Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum 62:1469–1477CrossRefPubMedGoogle Scholar
  15. 15.
    Abe J, Izawa K, Nishikomori R, Awaya T, Kawai T, Yasumi T, Hiragi N, Hiragi T, Ohshima Y, Heike T (2013) Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus. Rheumatology (Oxford) 52:406–408CrossRefGoogle Scholar
  16. 16.
    Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ (2011) Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A 155(A):235–237CrossRefGoogle Scholar
  17. 17.
    Grieves JL, Fye JM, Harvey S, Grayson JM, Hollis T, Perrino FW (2015) Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. Proc Natl Acad Sci USA 112:5117–5122CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rice GI, Rodero MP, Crow YJ (2015) Human disease phenotypes associated with mutations in TREX1. J Clin Immunol 35:235–243CrossRefPubMedGoogle Scholar
  19. 19.
    Stetson DB, Ko JS, Heidmann T, Medzhitov R (2008) Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–598CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kretschmer S, Wolf C, König N, Staroske W, Guck J, Häusler M, Luksch H, Nguyen ALA, Kim B, Alexopoulou D, Dahl A, Rapp A, Cardoso MC, Shevchenko A, Lee-Kirsch ME (2015) 1SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis 74:e17CrossRefPubMedGoogle Scholar
  21. 21.
    Munoz J, Rodière M, Jeremiah N, Rieux-Laucat F, Oojageer A, Rice GI, Rozenberg F, Crow YJ, Bessis D (2015) Stimulator of interferon genes-associated vasculopathy with onset in infancy: A mimic of childhood Granulomatosis with Polyangiitis. JAMA Dermatol 151:872–877CrossRefPubMedGoogle Scholar
  22. 22.
    Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg MC, Goudin N, Frémond ML, Nitschke P, Molina TJ, Blanche S, Picard C, Rice GI, Crow YJ, Manel N, Fischer A, Bader-Meunier B, Rieux-Laucat F (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest 124:5516–5520CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Baechler EC, Batliwalla FM, Karypis G et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 100:2610–2615CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chiche L, Jourde-Chiche N, Whalen E et al (2014) Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheum 66:1583–1595CrossRefGoogle Scholar
  25. 25.
    Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, Drappa J, Wang L, Greth W (2016) CD1067 study investigators. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: A randomised, double-blind, placebo-controlled study. Ann Rheum Dis 75:1909–1916CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Günther C, Schmidt F, König N, Lee-Kirsch MA (2016) Type I interferonopathies. Systemic inflammatory diseases triggered by type I interferons. Z Rheumatol 75:134–140CrossRefPubMedGoogle Scholar
  27. 27.
    Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, de Silva U, Bailey SL, Witte T, Vyse TJ, Kere J, Pfeiffer C, Harvey S, Wong A, Koskenmies S, Hummel O, Rohde K, Schmidt RE, Dominiczak AF, Gahr M, Hollis T, Perrino FW, Lieberman J, Hübner N (2007) Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39:1065–1067CrossRefPubMedGoogle Scholar
  28. 28.
    An J, Woodward JJ, Sasaki T, Minie M, Elkon KB (2015) Cutting edge: Antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction. J Immunol 194:4089–4093CrossRefPubMedGoogle Scholar
  29. 29.
    Tüngler V, König N, Günther C, Engel K, Fiehn C, Smitka M, von der Berner HMR, Lee-Kirsch MA (2016) Response to: ’JAK inhibition in STING-associated interferonopathy’ by Crow et al. Ann Rheum Dis 75:e76CrossRefPubMedGoogle Scholar
  30. 30.
    Frémond M‑L, Rodero MP, Jeremiah N et al (2016) Efficacy of the Janus kinase ½ inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol 138:1752–1755CrossRefPubMedGoogle Scholar
  31. 31.
    Rodero MP, Frémond ML, Rice GI, Neven B, Crow YJ (2016) JAK inhibition in STING-associated interferonopathy. Ann Rheum Dis 75:e75CrossRefPubMedGoogle Scholar
  32. 32.
    Wenzel J, van Holt N, Maier J, Vonnahme M, Bieber T, Wolf D (2016) AK1/2 inhibitor Ruxolitinib controls a case of chilblain lupus Erythematosus. J Investig Dermatology 136:1281–1283CrossRefGoogle Scholar
  33. 33.
    Hornung T, Janzen V, Heidgen FJ, Wolf D, Bieber T, Wenzel J (2014) Remission of recalcitrant dermatomyositis treated with ruxolitinib. N Engl J Med 371:2537–2538CrossRefPubMedGoogle Scholar
  34. 34.
    Jabbari A, Dai Z, Xing L, Cerise JE, Ramot Y, Berkun Y et al (2015) Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib. EBioMedicine 2:351–355CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.ACURA-Rheumazentrum Baden-BadenBaden-BadenDeutschland

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