Deep Immunophenotyping Reveals Distinct Immune Signatures in Axial Spondyloarthritis and Psoriatic Arthritis

Objective Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) are overlapping yet distinct conditions within the SpA spectrum. As divergent immunophenotypes may influence disease course and therapeutic response, we compared immune cell subsets, cytokine profiles, and inflammatory mediators. Methods Peripheral blood mononuclear cells (PBMCs) from 179 patients (88 axSpA, 91 PsA) and 49 healthy donors were profiled using spectral flow cytometry, comprising 230 million acquired events and 55 million quality‐controlled cells. Immune subsets, activation‐ and differentiation‐associated markers, and cytokines were analyzed to define disease‐specific profiles. Results axSpA and PsA exhibited distinct immunophenotypic profiles. axSpA was characterized by expansion of double‐negative and γδ T cells, increased plasmablasts and CD21 low B cells, and higher expression of activation‐associated markers (CD80, CD86, CD95), consistent with dysregulated innate‐like immune activation. PsA showed increased dendritic cells and a higher frequency of IgM + IgD − memory B cells. Both diseases exhibited Th1 enrichment; however, axSpA showed additional Th17 skewing and increased expression of activation‐ and checkpoint‐associated markers (HLA‐DR, CD38, PD‐1), whereas PsA displayed more central memory CD4 + T cells and lower PD‐1 expression. Cytokine profiling revealed elevated inflammasome‐related and innate cytokines in axSpA, whereas PsA showed increased soluble interleukin‐2 (IL‐2) receptor, IL‐17A, soluble tumor necrosis factor receptor type I, and vascular‐associated inflammatory mediators. Regularized regression identified a stable immune signature distinguishing axSpA from PsA (cross‐validated area under the receiver operating characteristic curve 0.94). Conclusion axSpA and PsA share overlapping yet distinguishable immunophenotypic signatures. axSpA shows enrichment of innate‐associated and broadly activated immune features, whereas PsA is characterized by adaptive and memory‐associated immune responses. These findings may support biomarker‐guided stratification within the SpA spectrum. image