Significance High-expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe joint destruction in autoimmune arthritis, but the mechanism for this effect is unknown. High-genotypic MIF -expressing joint fibroblasts produce high levels of MIF under inflammatory stimulation to up-regulate the surface expression of the MIF signaling coreceptor CD44 and promote its alternative splicing into invasive, tumor-associated isoforms, which contribute to the invasive and tissue-destructive character of the rheumatoid joint synovium. These findings support a precision medicine approach to the treatment of rheumatoid arthritis by pharmacologically targeting the MIF pathway in high-genotypic MIF -expressing patients.