Knee osteoarthritis phenotypes based on synovial fluid immune cells correlate with clinical outcome trajectories

Background Knee osteoarthritis (KOA) is a highly heterogeneous disease encompassing a wide range of clinical phenotypes. Phenotypes based on immune cells and protein pattern in synovial fluid (SF) and their relationship to clinical trajectories have not been described. Objective To assess phenotypes based on immune cells and protein pattern of SF in KOA. Design SF-derived immune cells were investigated in 119 patients with KOA using flow cytometry. Immune-phenotypes (iPhen) were determined by multivariate patient similarity network analysis and related to clinical trajectory (3–6 months post-sampling) along with protein pattern and macrophage chemokine receptors. Results Four iPhen were detected based on the distribution of T-lymphocytes, monocyte–macrophage lineage cells and activated CD8+ T-lymphocytes. The ‘activated’ phenotype (n = 17) had high T-lymphocytes but low monocyte–macrophage lineage cells and neutrophils, all highly activated, and showed improved symptoms in 70% patients. The ‘lymphoid progressive’ phenotype (n = 31) had high neutrophils, low lymphocytes and monocyte–macrophage lineage cells, low activation and was associated with lower pain levels. The ‘myeloid progressive’ phenotype (n = 35) had high NK and monocyte–macrophage lineage cells but low T-lymphocytes and activation. The ‘aggressive’ phenotype (n = 36) had high lymphocytes, macrophages, NK cells and neutrophils and high activation, and only 39% of patients improved during follow-up. Low CXCR4 and CCR7 expression on macrophages and high CXCL10 in SF were linked to improved clinical trajectory. Conclusion We identified four immune-phenotypes that were associated with different clinical trajectories in KOA patients. How these phenotypes can be targeted therapeutically deserves further investigation. Knee osteoarthritis (KOA) is a highly heterogeneous disease encompassing a wide range of clinical phenotypes. Phenotypes based on immune cells and protein pattern in synovial fluid (SF) and their relationship to clinical trajectories have not been described. To assess phenotypes based on immune cells and protein pattern of SF in KOA. SF-derived immune cells were investigated in 119 patients with KOA using flow cytometry. Immune-phenotypes (iPhen) were determined by multivariate patient similarity network analysis and related to clinical trajectory (3–6 months post-sampling) along with protein pattern and macrophage chemokine receptors. Four iPhen were detected based on the distribution of T-lymphocytes, monocyte–macrophage lineage cells and activated CD8+ T-lymphocytes. The ‘activated’ phenotype (n = 17) had high T-lymphocytes but low monocyte–macrophage lineage cells and neutrophils, all highly activated, and showed improved symptoms in 70% patients. The ‘lymphoid progressive’ phenotype (n = 31) had high neutrophils, low lymphocytes and monocyte–macrophage lineage cells, low activation and was associated with lower pain levels. The ‘myeloid progressive’ phenotype (n = 35) had high NK and monocyte–macrophage lineage cells but low T-lymphocytes and activation. The ‘aggressive’ phenotype (n = 36) had high lymphocytes, macrophages, NK cells and neutrophils and high activation, and only 39% of patients improved during follow-up. Low CXCR4 and CCR7 expression on macrophages and high CXCL10 in SF were linked to improved clinical trajectory. We identified four immune-phenotypes that were associated with different clinical trajectories in KOA patients. How these phenotypes can be targeted therapeutically deserves further investigation.