Background/Purpose: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by mutations in the nucleases TREX1 or SAMHD1. The adapter molecule stimulator of interferon genes (STING) mediates DNA-induced activation of type I interferon (IFN) through binding of its ligand cyclic GMP-AMP (cGAMP). De novo STING mutations cause STING-associated vasculopathy with onset in infancy (SAVI), an autoinflammatory syndrome with vascular, cutaneous and pulmonary manifestations.

Methods: Clinical and genetic characterization of a large non-consanguineous family with chilblain lupus. Identification of the disease gene by exome sequencing. Analysis of skin histology. Functional testing of transfected wild type and mutant STING-cDNA on type I IFN activation. Evaluation of the response to short-term treatment with the JAK inhibitor tofacitimib on the transcriptional signature of IFN-induced genes in blood cells by quantitative RT-PCR.

Results: Five members of the family spanning four generations suffered from chilblain lupus since early childhood. Cold-induced inflammatory chilblain lesions were located at acral locations including fingers, toes, nose, ears, elbows and shins. Lesions presented as bluish-red infiltrations and led to mutilating necrotic ulcerations. In some patients, low-titred ANA and immune complexes were detectable; the skin histology was characterized by perivascular infiltrates and high MxA expression. Affected family members also exhibited increased expression of IFN-stimulated genes in blood. Mutations in TREX1 and SAMHD1 were excluded in the family. Exome sequencing identified a heterozygous STING mutation co-segregating with chilblain lupus. This previously unknown mutation affects a conserved amino acid residue located within the STING dimer interface and is predicted to be deleterious. Mutant STING-cDNA transfected into HEK cells led to phosphorylation of IRF3 and IFN-β production even in the absence of cGAMP stimulation. Treatment of two affected family members with the JAK inhibitor tofacitinib at 5 mg bid for 14 days led to a significant suppression of the transcriptional signature of IFN-induced genes in blood and to relief of symptoms of acral ischemia.

Conclusion: This is the first report of a family with dominant chilblain lupus due to an activating mutation of STING and expands the spectrum of type I interferonopathies. Suppression of chronically activated type I IFN signaling through inhibition of the JAK/STAT pathway with tofacitinib may represent a promising new therapeutic approach.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dominant-chilblain-lupus-due-to-an-activating-mutation-of-sting-suppression-of-constitutive-type-i-interferon-activation-by-jak-inhibition/