Activation of the interferon‐α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease

Abstract

Gene-expression studies have demonstrated increased expression of interferon (IFN)-inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN. This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway. Freshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real-time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFNalpha, and the data were used to derive IFNalpha scores for all individuals. Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors. SLE patients with high and low IFNalpha scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses. SLE patients with a high IFNalpha score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFNalpha scores. Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score. The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFNalpha score. Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti-RNA binding protein (RBP) autoantibodies were associated with a high IFNalpha score. Activation of the IFNalpha pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP.