Familial Chilblain Lupus - What Can We Learn from Type I Interferonopathies?
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.
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.
KeywordsChilblain lupus hereditary STING Interferon JAK inhibitors
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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
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- 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.•• 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
- 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.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
- 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.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
- 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.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
- 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
- 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.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
- 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.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.• 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.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.• 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
- 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