Two Distinct Phenotypes of Takayasu Arteritis Associated With TNF-α and IL-6: Implications for Endotype-driven Precise Therapy

Background Tumour necrosis factor (TNF)-α and interleukin (IL)-6 play central roles in the pathogenesis of Takayasu arteritis (TAK). In this study we aimed to characterize the clinical phenotypes and identify effective treatments for TAK on the basis of different expression patterns of TNF-α and IL-6. Methods A total of 486 TAK patients were stratified into 4 groups on the basis of the expression pattern of TNF-α and IL-6: normal levels of both cytokines; elevated TNF-α only; elevated IL-6 only; and elevation of both cytokines. We analyzed clinical and immune phenotypes and effective treatments across groups. Efficacy of a stratified treatment strategy was further prospectively validated in 20 patients. Results Patients in 4 groups exhibited different inflammatory types: silent, smoldering, active, and severe. Specifically, elevated TNF-α level was associated with a vascular-dominant symptom phenotype, characterized by more severe stenosis with mild vascular inflammation, enrichment of cluster of differentiation (CD)-19+ B cells and monocytes, and a relatively higher complete remission (CR) rate. In contrast, elevated IL-6 level was linked to an active inflammatory phenotype, featuring prominent constitutional symptoms, severe vascular inflammation and wall thickening, elevated inflammatory marker levels, enrichment of CD8+ T cells, and a relatively lower CR rate. Four groups of patients responded well to 4 distinct regimens: glucocorticoids combined with tofacitinib, adalimumab, tofacitinib, and tocilizumab, respectively. An impressive 83.33% CR rate with glucocorticoid dose of only 7.5 mg/d was achieved at 6 months in the prospective validation patients. Conclusions TNF-α and IL-6 are associated with distinct clinical and immunological phenotypes of TAK and differential treatment responses, providing a basis for endotype-driven, precision therapy in patients with TAK. Clinical Trial Registration NCT03893136.