Familial Chilblain Lupus - What Can We Learn from Type I Interferonopathies?

  • Christoph FiehnEmail author
Orphan Diseases (B Manger, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Orphan Diseases


Purpose of Review

Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms.

Recent Findings

There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described. These genes are involved in the process of the detection of intracellular DNA, and their mutation results in an increased production of type I interferons and their gene products, resulting in auto-inflammation and auto-immunity. JAK inhibitors have been successfully used to treat this disorder.


Familial chilblain is a rare disorder with very distinct clinical signs. Its pathophysiological mechanism gives insight into the process of interferon-induced inflammation in auto-immune diseases.


Chilblain lupus hereditary STING Interferon JAK inhibitors 


Compliance with Ethical Standards

Conflict of Interest

Dr. Fiehn declares he has no conflicts to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y AcadSci. 2011;1238:91–8.CrossRefGoogle Scholar
  2. 2.
    Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med. 2016;213:2527–38.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    • Lee-Kirsch MA, Wolf C, Kretschmer S, et al. Type I interferonopathies: an expanding disease spectrum of immunodysregulation. Semin Immunopathol. 2015;37:349–57. A comprehensive overview of the type I interferonopathies with a focus on its genetic mechanisms.Google Scholar
  4. 4.
    •• König N, Fiehn C, Wolf C, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2016;76(2):468–72. The most recent description of a family with familiar chilblain lupus due a mutation of STING and the analysis of the molecular mechanism.Google Scholar
  5. 5.
    Padeh S, Gerstein M, Greenberger S, Berkun Y. Chronic chilblains: the clinical presentation and disease course in a large paediatric series. Clin Exp Rheumatol. 2013;31:463–8.PubMedGoogle Scholar
  6. 6.
    •• Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18. The first description of SAVI-Syndrome, a systemic disease with multiorgan involvement due to mutations of STING.Google Scholar
  7. 7.
    Picard C, Thouvenin G, Kannengiesser C, Dubus JC, Jeremiah N, Rieux-Laucat F, et al. Severe pulmonary fibrosis as the first manifestation of interferonopathy (TMEM173 Mutation). Chest. 2016;150:e65–71.Google Scholar
  8. 8.
    Gray EE, Treuting PM, Woodward JJ, Stetson DB. Cutting Edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutières syndrome. J Immunol. 2015;195:1939–43.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Günther C, Hillebrand M, Brunk J, Lee-Kirsch MA. Systemic involvement in TREX1-associated familial chilblain lupus. J Am Acad Dermatol. 2013;69:e179–81.CrossRefPubMedGoogle Scholar
  10. 10.
    Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;80:811–5.Google Scholar
  11. 11.
    Lee-Kirsch MA, Gong M, Schulz H, Rüschendorf F, Stein A, Pfeiffer C, et al. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet. 2006;79:731–7.Google Scholar
  12. 12.
    Günther C, Berndt N, Wolf C, Lee-Kirsch MA. Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1). JAMA Dermatol. 2015;151:426–31.CrossRefPubMedGoogle Scholar
  13. 13.
    Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K, Hunger S, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum. 2010;62:1469–77.Google Scholar
  14. 14.
    Abe J, Izawa K, Nishikomori R, Awaya T, Kawai T, Yasumi T, et al. Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus. Rheumatology (Oxford). 2013;52:406–8.Google Scholar
  15. 15.
    Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984;15:49–54.CrossRefPubMedGoogle Scholar
  16. 16.
    Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A. 2011;155A:235–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. J Clin Immunol. 2015;35:235–43.CrossRefPubMedGoogle Scholar
  18. 18.
    Grieves JL, Fye JM, Harvey S, Grayson JM, Hollis T, Perrino FW. Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. Proc Natl Acad Sci U S A. 2015;112:5117–22.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic Initiation of autoimmunity. Cell. 2008;134:587–98.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kretschmer S, Wolf C, König N, Staroske W, Guck J, Häusler M, et al. 1SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis. 2015;74:e17.Google Scholar
  21. 21.
    Chiche L, Jourde-Chiche N, Whalen E, et al. Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheum. 2014;66:1583–95.CrossRefGoogle Scholar
  22. 22.
    Baechler EC, Batliwalla FM, Karypis G, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA. 2003;100:2610–5.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:1909–16.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39:1065–7.Google Scholar
  25. 25.
    Günther C, Schmidt F, König N, Lee-Kirsch MA. Type I interferonopathies. Systemic inflammatory diseases triggered by type I interferons. Z Rheumatol. 2016;75:134–40.CrossRefPubMedGoogle Scholar
  26. 26.
    An J, Woodward JJ, Sasaki T, Minie M, Elkon KB. Cutting edge: Antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction. J Immunol. 2015;194:4089–93.CrossRefPubMedGoogle Scholar
  27. 27.
    Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg MC, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124:5516–20.Google Scholar
  28. 28.
    Munoz J, Rodière M, Jeremiah N, Rieux-Laucat F, Oojageer A, Rice GI, et al. Stimulator of interferon genes-associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol. 2015;151:872–7.Google Scholar
  29. 29.
    • Tüngler V, König N, Günther C, Engel K, Fiehn C, Smitka M, et al. Response to: 'JAK inhibition in STING-associated interferonopathy' by Crow et al. Ann Rheum Dis. 2016;75:e76. Description of patients with Aicardi–Goutières syndrome treated with the JAK inhibitor ruxolitinib.Google Scholar
  30. 30.
    Frémond M-L, Rodero MP, Jeremiah N, et al. 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. 2016; 138(6):1752–5.Google Scholar
  31. 31.
    • Rodero MP, Frémond ML, Rice GI, Neven B, Crow YJ. JAK inhibition in STING-associated interferonopathy. Ann Rheum Dis. 2016;75:e75. Response to König et al. and discussion of the long-term efficiency of JAK inhibitors for interferonopathies.Google Scholar
  32. 32.
    Wenzel J, van Holt N, Maier J, Vonnahme M, Bieber T, Wolf D. AK1/2 Inhibitor Ruxolitinib Controls a Case of Chilblain Lupus Erythematosus. Journal of Investigative Dermatology. 2016;136:1281–3.CrossRefPubMedGoogle Scholar
  33. 33.
    Hornung T, Janzen V, Heidgen FJ, Wolf D, Bieber T, Wenzel J. Remission of recalcitrant dermatomyositis treated with ruxolitinib. N Engl J Med. 2014;371:2537–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Jabbari A, Dai Z, Xing L, Cerise JE, Ramot Y, Berkun Y, et al. Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib. E Bio Medicine. 2015;2:351–5.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Unit for Rheumatology and Clinical ImmunologyMedical Center Baden-BadenBaden-BadenGermany

Personalised recommendations