OBJECTIVE: Type I interferon (IFN) is implicated in the pathogenesis of systemic 
lupus erythematosus (SLE) and interferonopathies such as Aicardi-Goutières 
syndrome. A recently discovered DNA-activated type I IFN pathway, cyclic GMP-AMP 
synthase (cGAS), has been linked to Aicardi-Goutières syndrome and mouse models 
of lupus. The aim of this study was to determine whether the cGAS pathway 
contributes to type I IFN production in patients with SLE.
METHODS: SLE disease activity was measured by the Safety of Estrogens in Lupus 
Erythematosus National Assessment version of the Systemic Lupus Erythematosus 
Disease Activity Index. Expression of messenger RNA for cGAS and IFN-stimulated 
genes (ISGs) was determined by quantitative polymerase chain reaction analysis. 
Cyclic GMP-AMP (cGAMP) levels were examined by multiple reaction monitoring with 
ultra-performance liquid chromatography tandem mass spectrometry.
RESULTS: Expression of cGAS in peripheral blood mononuclear cells (PBMCs) was 
significantly higher in SLE patients than in normal controls (n = 51 and n = 20 
respectively; P < 0.01). There was a positive correlation between cGAS 
expression and the IFN score (P < 0.001). The expression of cGAS in PBMCs showed 
a dose response to type I IFN stimulation in vitro, consistent with it being an 
ISG. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 
15% of the SLE patients (7 of 48) but none of the normal (0 of 19) or rheumatoid 
arthritis (0 of 22) controls. Disease activity was higher in SLE patients with 
cGAMP versus those without cGAMP.
CONCLUSION: Increased cGAS expression and cGAMP in a proportion of SLE patients 
indicates that the cGAS pathway should be considered as a contributor to type I 
IFN production. Whereas higher cGAS expression may be a consequence of exposure 
to type I IFN, detection of cGAMP in patients with increased disease activity 
indicates potential involvement of this pathway in disease expression.