Cytokine-involved phenotyping identifies a high-risk inflammatory cluster in treatment-naïve Takayasu's arteritis

Takayasu's arteritis (TAK) is a clinically heterogeneous large-vessel vasculitis. Conventional inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may not adequately reflect underlying immune activation or predict long-term outcomes. We aimed to identify immune phenotypes based on serum cytokine profiles and evaluate their clinical relevance in treatment-naïve TAK.

We performed an unsupervised two-step cluster analysis in a cohort of 95 treatment-naïve patients with TAK. Serum levels of 12 cytokines were measured at baseline and clustering incorporated cytokine profiles together with selected clinical variables, including age at onset, disease duration, ESR and CRP. Clinical outcomes were evaluated using multivariable Cox regression models adjusting for disease duration and treatment exposure. A cytokine-involved scoring system was developed for phenotype classification and internally evaluated.

Three distinct immune phenotypes were identified. Cluster 2 exhibited multiplex cytokine activation, characterised by elevated interleukin (IL)-1β, IL-2, IL-4, IL-10, tumour necrosis factor-α (TNF-α) and interferon (IFN)-α with the worst outcomes: high relapse (50.0%), refractory disease (41.7%), and mortality (16.7%). Cluster 1 showed an acute phase response (high ESR, CRP, IL-6, IFN-γ), more active disease, and increased relapse risk (41.7%). Cluster 3 had a noninflammatory phenotype, the highest remission (74.5%), and lowest relapse (4.3%). A cytokine-involved scoring model accurately classified phenotype (accuracy 85.2%, AUC 0.964).

Cytokine-involved phenotyping may provide a preliminary framework for risk stratification in treatment-naïve TAK. The multiplex cytokine activation phenotype appears to be associated with adverse clinical outcomes, although further validation in larger cohorts is required.