Endotypes, phenotypes, and biomarkers in chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) is an inflammatory disorder that manifests with hives, angioedema, or both and lasts more than or equal to 6 weeks. Although certain elements of CSU pathogenesis are well defined, others remain unclear. We discuss our current understanding of the 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, namely type I (autoallergic) and type IIb (autoimmune). However, a subpopulation shows 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 the identified biomarkers, genetic risk loci, phenotypes, and corresponding endotypes, and each of these is frequently considered independently of the others. These identifiable features also have 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 the 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.