Interferon and interferon-induced cytokines as markers of impending clinical progression in ANA+ individuals without a systemic autoimmune rheumatic disease diagnosis

BackgroundElevated levels of interferons (IFNs) are a characteristic feature of systemic autoimmune rheumatic diseases (SARDs) and may be useful in predicting impending symptomatic progression in anti-nuclear antibody-positive (ANA(+)) individuals lacking a SARD diagnosis. Typically, these are measured by their effect on gene expression in the blood, which has limited their utility in clinical settings. Here, we assessed whether the measurement of serum IFN-alpha or selected IFN-induced cytokines accurately mirrors IFN-induced gene expression in ANA(+) individuals and investigated their utility as biomarkers of clinical progression.MethodsA total of 280 subjects were studied, including 50 ANA(-) healthy controls, 160 ANA(+) individuals without a SARD diagnosis (96 asymptomatic, 64 with undifferentiated connective tissue disease), and 70 SARD patients. IFN-induced gene expression was measured by nanoString and cytokine levels by ELISA or Simoa. ANA(+) individuals lacking a SARD diagnosis who had the new onset of SARD criteria over the subsequent 2 years were defined as progressors.ResultsMeasurement of IFN-alpha levels by high-sensitivity ELISA or Simoa correlated much better with IFN-induced gene expression than measurement of CXCL-10 or Galectin-9 levels. Despite this, high CXCL-10 and Galectin-9 levels were better predictors of subsequent progression in ANA(+) individuals than measures of IFN-alpha or IFN-induced gene expression with the optimal combination of predictive cytokines (CXCL-10 and IFN-alpha as measured by ELISA), resulting in a specificity and positive predictive value of 100%.ConclusionEasily performed ELISA assays for CXCL-10 and IFN-alpha can be used to predict ANA(+) individuals at high risk of imminent symptomatic progression.