We describe the prevalence of the systemic IFN type I signature in over one-half of pSS patients (referred to as IFN-positive pSS), identifying a subgroup of patients with higher European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores, presence of anti-Sjögren’s syndrome-associated autoantigen SSA (Ro52 and Ro60) and/or anti-Sjögren’s syndrome-associated autoantigen SSB (La) autoantibodies, higher immunoglobulin (Ig) G and B-cell activating factor (BAFF) levels, and lower C3 complement levels [10]. The gene discussed is TRIM21; the disease is Down syndrome.