The underlying molecular mechanisms are diverse and include abnormal accumulation of endogenous nucleic acids as in Aicardi-Goutières syndrome and familial chilblain lupus (4), enhanced sensitization of IFN-I receptors (IFNARs) as in STING-associated vasculopathy with onset in infancy (SAVI; ref. 5), enhanced IFN-I gene transcription due to gain of function of STAT2 (6, 7), and defective negative regulation of IFN-I due to loss of IFN-stimulated gene 15 (ISG15; ref. 8) or ubiquitin-specific peptidase 18 (USP18; ref. 9) (reviewed in refs. 3, 10). Here, USP18 is linked to familial chilblain lupus.