Endotypes, phenotypes, and biomarkers in chronic spontaneous urticaria: Evolving toward personalized medicine

Chronic spontaneous urticaria (CSU) is an inflammatory disorder manifesting with hives, angioedema, or both, and lasting ≥6 weeks. Although certain elements of CSU pathogenesis are well defined, others remain unclear. We discuss our current understanding of underlying CSU endotypes, distinct clinical phenotypes, and predictive biomarkers. It is increasingly recognized that CSU comprises a spectrum of different underlying pathogenic mechanisms and distinct clinical presentations. Broadly, 2 endotypes that drive CSU pathogenesis have been identified: type I (autoallergic) and type IIb (autoimmune). However, a subpopulation has evidence of both types, and some patients show evidence of neither. Multiple identified biomarkers have been associated with these endotypes or with disease features such as CSU severity and duration. There is a lack of connectivity among identified biomarkers, genetic risk loci, phenotypes, and corresponding endotypes, with each frequently considered independently of the others. These identifiable features have also been associated with response, or lack thereof, to available therapies. Future investigations should optimize the endotyping of CSU using point-of-care, noninvasive, accessible biomarkers and assess differences in response to therapy. With multiple treatments in late-stage development, establishing clearly defined CSU endotypes will facilitate future treatment decision-making and tailored treatment approaches, and will inform optimal trial design.