Elevated Cytokines in Varicose Veins But Not Venous Ulcers Suggest Immunologic Exhaustion in Venous Leg Ulcers

Inflammatory changes within varicose veins can result in skin complications including venous leg ulcer (VLU). We have previously proposed that cytokines involved in T cell activation are markers of disease and may be targets to attenuate disease progression. Here, we measured circulating cytokines within varicose veins and from subjects with and without venous leg ulcer. We hypothesized that cytokines associated with T cell activation including interferon gamma (IFN-γ), IL-2, and IL-12p70 would be elevated in varicose vein and VLU patients. Venous blood was obtained from the antecubital fossa or from superficial leg veins from subjects without venous disease, with varicose veins with or without concomitant leg swelling or skin discoloration (CEAP clinical class C 2-4), and with healed or active venous ulcers (CEAP C5-6). Plasma was processed for IFN-γ, IL-2, and IL-12p70 using enzyme-linked immunosorbent assay and/or Luminex multiplex analysis. Individual concentrations were compared among the groups using analysis of variance with post hoc Tukey's multiple comparisons test. Statistical significance was set at a P value of <.05. Cytokine levels were measured among subjects without venous disease (n = 76), with varicose veins characterizing C2-4 disease (n = 51) and with healed or active venous leg ulcer characterized by C5-6 disease (n = 22). Age was similar among groups and female subjects predominated. IFN-γ, IL-2, and IL-12p70 were significantly elevated in plasma from C2-4 disease when compared with both C5-6 disease and asymptomatic subjects (P < .001 and .0001; Figure). Surprisingly, only C2-4 disease encompassing varicose veins without venous leg ulcer demonstrated elevated cytokine levels associated with T cell-mediated immunity. Active or healed venous leg ulcer did not demonstrate similarly elevated inflammatory markers despite the history of tissue loss. These data suggest that VLU may be associated with an exhausted immune state associated with T-cell dysfunction in the setting of chronic wounds.