Depressed Inflammatory Mediators May Suggest Immunologic Dysregulation in Advanced Venous Disease

Venous ulcer disease are slow to heal, recur frequently and represent a significant burden to the global healthcare system. In similar diseases such as diabetic foot ulcers, a lack of a robust inflammatory response frustrates wound healing. We do not know if a similar phenomenon occurs in venous ulcer. In this study we used circulating plasma cytokine concentrations to understand how inflammation might link with venous leg ulcer. We hypothesized that venous leg ulcer may be associated with a less robust inflammatory response in regard to T cell activity which could explain in part their refractory nature, acknowledging the influence of factors such as obesity, venous hypertension, and pelvic outflow obstruction.

Human subjects with CEAP clinical class 2-6 chronic venous disease undergoing treatment, and control subjects without venous insufficiency were included. Demographic information, including age, gender, race/ethnicity, and comorbidities, were recorded. Descriptive statistics were calculated for each group. Plasma was obtained from venipuncture in treated and control subjects for isolation of cytokines using ELISA and multiplex techniques with a focus on IFN-γ, IL12 and IL2 levels which are associated with T cell activity. Multiple linear regression was used to correlate cytokine level with clinical disease status, focusing on correlations with IL2 which can help determine T cell fate.

Subjects with C₂-C₄ disease demonstrated significantly elevated plasma levels of the T-cell associated cytokines IFN-γ, IL12p70 and IL2 compared to both control subjects and those subjects with C₅-C₆ disease. Multilinear regression suggested that presentation with C₂-C₄ disease, IFN-γ and IL12p70 concentrations significantly predicted IL2 concentration while VCSS scores, age, sex, DM, and smoking did not.

Higher cytokine levels were primarily seen in subjects with varicose veins (C₂-C₄) as opposed to those with chronic wounds (C₅-C₆) which supports a reason why venous leg ulcer healing may stall. IL-2 is a regulator of T cell activity and as not only diminished in venous ulcer disease but was also correlated with other T cell mediators such as IFN-γ and IL12p70. T cell exhaustion, characterized by a declining immune response in the setting of antigen hyperstimulation and a reduced ability to carry out essential immune functions may be a reason explain these findings. Targeting T helper cell activity may be a future therapeutic avenue for managing severe chronic venous disease.