Biological Profile of Primary and Secondary Lymphedema: Inflammatory, Endothelial, Metabolic, Lymphatic, and Fibrotic Markers
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Serum IL-13 concentrations
研究概览
简要总结
This observational, cross-sectional study aims to characterize the biological profile of primary and secondary lymphedema by investigating five interconnected biological domains: T helper 2 (Th2)-related inflammation, endothelial activation, metabolic dysfunction, lymphatic biology, and tissue fibrosis.
Lymphedema is traditionally considered a disorder of impaired lymphatic drainage resulting in the accumulation of interstitial fluid. However, increasing evidence suggests that its development and progression involve chronic inflammation, endothelial dysfunction, metabolic alterations, abnormal lymphatic signaling, adipose tissue accumulation, and progressive tissue fibrosis. While these mechanisms have been investigated predominantly in secondary lymphedema, the systemic biological profile of primary lymphedema remains insufficiently characterized.
The study will include approximately 90 participants aged 18-45 years: 30 participants with primary lymphedema, 30 participants with secondary lymphedema, and 30 healthy control participants matched by age and sex. Each participant will attend one study visit lasting approximately 45-60 minutes.
Clinical assessment will include medical history, demographic characteristics, blood pressure, body measurements, assessment of lymphedema location and clinical stage, pitting edema, Stemmer sign, skin changes, limb volume measurement by perometry, and assessment of tissue firmness. Venous blood samples will be collected to assess routine laboratory parameters and a panel of inflammatory, endothelial, metabolic, lymphatic, and fibrotic biomarkers. A standardized skin swab will also be collected for exploratory skin microbiome analysis.
For the primary analysis, one representative marker will be selected in advance for each of the five biological domains: interleukin-13 (IL-13) for Th2-related inflammatory activity, soluble vascular cell adhesion molecule-1 (sVCAM-1) for endothelial activation, homeostatic model assessment of insulin resistance (HOMA-IR) for metabolic dysfunction, vascular endothelial growth factor C (VEGF-C) for lymphatic biology, and transforming growth factor beta 1 (TGF-β1) for tissue fibrosis. These five variables will constitute the co-primary outcome measures.
Secondary analyses will evaluate additional biomarkers within each biological domain and their associations with clinical severity, including lymphedema stage, limb volume, pitting edema, Stemmer sign, and skin fibrosis. The study will also investigate relationships between the different biological domains and assess differences between primary and secondary lymphedema.
Exploratory analyses will characterize the skin microbiome of affected and standardized comparison sites and investigate associations between microbiome composition, clinical disease characteristics, and systemic biomarkers. In participants with primary lymphedema without a previously established genetic diagnosis, selected genetic variants associated with primary lymphedema will also be investigated.
The study will provide a comprehensive assessment of biological alterations associated with lymphedema and may help clarify differences between primary and secondary disease. The findings may contribute to a better understanding of lymphedema as a complex biological and tissue disorder and provide a basis for future studies of more targeted diagnostic and therapeutic approaches.
详细描述
- Background and Rationale Lymphedema is a chronic disorder characterized by impaired lymphatic transport and accumulation of interstitial fluid and macromolecules in affected tissues. It may be primary, resulting from congenital or genetically determined abnormalities of lymphatic development or function, or secondary, resulting from acquired damage to lymphatic vessels or lymph nodes. Secondary lymphedema may occur after cancer treatment, surgery, radiation therapy, trauma, infection, or other conditions that disrupt lymphatic drainage.
Although impaired lymphatic drainage is central to the clinical phenotype, current evidence indicates that lymphedema is not solely a mechanical disorder. Persistent lymphatic dysfunction may induce a complex tissue response involving immune activation, endothelial dysfunction, metabolic alterations, adipose tissue accumulation, abnormal lymphangiogenic signaling, extracellular matrix remodeling, and progressive fibrosis. These processes may interact with each other and contribute to disease progression and clinical heterogeneity.
The inflammatory response in lymphedema is characterized by infiltration and activation of immune cells and changes in cytokine signaling. In particular, type 2 immune responses and T helper 2 (Th2)-associated cytokines have been implicated in chronic inflammation and fibrosis. Endothelial activation may further contribute to altered vascular permeability and inflammatory cell recruitment. At the same time, metabolic and adipose tissue alterations may develop within chronically affected tissues and may also be reflected by systemic metabolic markers.
Changes in lymphatic biology are another important component of disease pathogenesis. Lymphatic endothelial cells and their signaling pathways regulate lymphatic vessel formation, maintenance, and function. Vascular endothelial growth factors and their receptors, particularly the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 (VEGF-C/VEGFR-3) pathway, are important regulators of lymphangiogenesis. Abnormal regulation of these pathways may reflect an attempt to compensate for impaired lymphatic function but may not be sufficient to restore effective lymphatic transport.
Progressive fibrosis represents an important late consequence of chronic lymphedema. Persistent inflammation and tissue remodeling may stimulate fibroblast activation and extracellular matrix deposition, resulting in increasing tissue stiffness and structural changes. Transforming growth factor beta and matrix metalloproteinases are among the pathways potentially involved in this process.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •General inclusion criteria for all participants:
- •Adults aged 18 to 45 years.
- •Ability to understand the study information and provide written informed consent.
- •Willingness and ability to attend one study visit and undergo the planned clinical assessment, blood sampling, and skin swab collection.
- •Additional inclusion criteria for participants with primary lymphedema:
- •Clinically and, where appropriate, imaging-confirmed primary lymphedema of an upper or lower extremity.
- •Lymphedema classified as Stage I or II according to the applicable clinical classification. Participants with Stage III disease may be included if disease progression is associated with recurrent cellulitis or erysipelas and this is documented separately.
- •Current treatment or follow-up at the Department of Dermatovenereology, University Medical Centre Ljubljana.
- •Additional inclusion criteria for participants with secondary lymphedema:
- •Clearly established acquired cause of lymphedema.
- •Comparable anatomical location and, where feasible, disease stage to the primary lymphedema group.
- •Completion of active oncological treatment, where secondary lymphedema is cancer-related.
- •Healthy control participants:
- •No clinical signs or previous history of lymphedema.
- •Comparable age and sex distribution to the lymphedema groups.
排除标准
- •Other major causes of limb swelling, including heart failure, nephrotic syndrome, clinically significant thyroid disease, or medications likely to cause edema when the effect cannot be adequately accounted for.
- •Acute systemic infection or cellulitis/erysipelas within 4 weeks before study enrollment.
- •Pregnancy or breastfeeding.
- •Active oncological treatment.
- •Active smoking.
- •Active inflammatory skin disease that could substantially affect the skin microbiome or systemic inflammatory biomarkers.
- •Clinically manifest cardiovascular disease or previous cardiovascular event.
- •Treatment with medications that are expected to substantially affect the selected immunological or metabolic outcomes when their effects cannot be adequately accounted for in the analysis.
- •Inability to provide valid informed consent.
- •Gender eligibility:
- •- Eligibility is not restricted by gender identity. Biological sex will be recorded where relevant for clinical and laboratory analyses, including sex-specific calculation of selected metabolic indices.
- •Withdrawal:
- •Participants may withdraw from the study at any time without providing a reason and without any effect on their subsequent medical care.
结局指标
主要结局
Serum IL-13 concentrations
时间窗: At the study visit (baseline)
Comparison of serum IL-13 concentrations among participants with primary lymphedema, secondary lymphedema, and healthy controls. IL-13 represents Th2-related inflammatory activity.
Serum sVCAM-1 concentration
时间窗: At the study visit (baseline)
Comparison of serum sVCAM-1 concentrations among the three study groups as a marker of endothelial activation.
HOMA-IR
时间窗: At the study visit (baseline)
Comparison of HOMA-IR among the three study groups as a measure of metabolic dysfunction.
Serum VEGF-C concentration
时间窗: At the visit (baseline)
Comparison of serum VEGF-C concentrations among the three study groups as a marker of lymphatic biology.
Serum TGF-β1 concentration
时间窗: At the study visit (baseline)
Comparison of serum TGF-β1 concentrations among the three study groups as a marker of tissue fibrosis.
次要结局
- Comparison of primary and secondary lymphedema(At the study visit (baseline))
研究者
Eva Klara Merzel Šabović
Eva Klara Merzel Šabović, MD, PhD, Principal Investigator
University Medical Centre Ljubljana