Discovery of molecular rheumatic disease subtypes. Schematic overview of the discovery of rheumatic disease subtypes in peripheral blood cells and affected target tissues. Heterogeneity in rheumatic diseases have been demonstrated at peripheral blood as well as tissue level using high-throughput genomics technology. Several studies have described the presence of at least two subgroups of patients based on the presence or absence of an activated type I interferon (IFN) induced gene expression profile in peripheral blood as well as in affected tissues. In addition, peripheral blood cells of rheumatic patients exhibit heterogeneous expression levels for genes involved in granulopoiesis and monocyte activation, as well as for genes encoding the inflammatory S100 proteins. Moreover, subsets of patients exhibit gene expression profiles similar to pathogen-induced profiles. Apart from type I IFN, tissue heterogeneity is reflected at the level of lymphoid neogenesis, fibrosis, myofibroblasts, tissue remodelling and transforming growth factor (TGF)-β signalling. The exact relationship between the peripheral blood profile and tissue profile needs to be further investigated.