Biological Profile of Primary and Secondary Lymphedema: Inflammatory, Endothelial, Metabolic, Lymphatic, and Fibrotic Markers

NCT07770399 | Not Yet Recruiting

• 1 other identifier: UKCL-LYMPH-2026
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Primary Lymphedema; Secondary Lymphedema

Keywords

lymphedema; primary lymphedema; secondary lymphedema; inflammation; endothelial activation; metabolic dysfunction; tissue fibrosis; skin microbioma

Outcome Measures

Primary Outcomes (5)

• Serum IL-13 concentrations

  Comparison of serum IL-13 concentrations among participants with primary lymphedema, secondary lymphedema, and healthy controls. IL-13 represents Th2-related inflammatory activity.

  At the study visit (baseline)

• Serum sVCAM-1 concentration

  Comparison of serum sVCAM-1 concentrations among the three study groups as a marker of endothelial activation.

  At the study visit (baseline)

• HOMA-IR

  Comparison of HOMA-IR among the three study groups as a measure of metabolic dysfunction.

  At the study visit (baseline)

• Serum VEGF-C concentration

  Comparison of serum VEGF-C concentrations among the three study groups as a marker of lymphatic biology.

  At the visit (baseline)

• Serum TGF-β1 concentration

  Comparison of serum TGF-β1 concentrations among the three study groups as a marker of tissue fibrosis.

  At the study visit (baseline)

Secondary Outcomes (1)

• Comparison of primary and secondary lymphedema

  At the study visit (baseline)

Other Outcomes (2)

• Skin microbiome composition

  At the study visit (baseline)

• Genetic variants associated with primary lymphedema

  At the study visit (baseline)

Study Arms (3)

Primary lymphedema

30 patients aged 18-35 years with primary lymphedema

Patients with secondary lymphedema

30 patients aged 18-35 years with secondary lymphedema

Controls

30 controls aged 18-35 years without lymphedema

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

The study will include approximately 90 adults aged 18-45 years, comprising three groups: 30 participants with primary lymphedema, 30 participants with secondary lymphedema, and 30 healthy controls without lymphedema. Participants with lymphedema will be recruited primarily from patients receiving care at the Department of Dermatovenereology, University Medical Centre Ljubljana. Healthy controls will be recruited through public or direct invitations without undue influence. The study groups will be comparable with respect to age and sex where feasible. Each participant will undergo a single study visit including clinical assessment, blood sampling, and standardized skin swab collection. The study is designed as an observational cross-sectional comparative study to characterize and compare biological and clinical features of primary and secondary lymphedema.

You may qualify if:

• 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.
• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead

Study Sites (1)

Clinic of Dermatovenereology, University Medical Centre Ljubljana

Ljubljana, 1000, Slovenia

Location

Biospecimen

Retention: SAMPLES WITH DNA

Venous blood samples, including serum, plasma, and whole blood, will be retained for the analysis of inflammatory, endothelial, metabolic, lymphatic, and fibrotic biomarkers. Where applicable, EDTA-anticoagulated whole blood will also be retained for exploratory genetic analysis in participants with primary lymphedema. Skin swab samples will be retained for microbiome analysis. Samples will be stored under controlled conditions for the period specified in the study protocol and laboratory procedures.

MeSH Terms

Conditions

Lymphedema; Inflammation

Condition Hierarchy (Ancestors)

Lymphatic Diseases; Hemic and Lymphatic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Tanja Planinšek Ručigaj, MD, PhD

  Clinic of Dermatovenereology, University Medical Centre Ljubljana

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tanja Planinšek Ručigaj, MD, PhD

CONTACT

+38615224280; tanja.planinsekrucigaj@kclj.si

Eva Klara Merzel Šabović, MD, PhD

CONTACT

+38615224280; eva.klara.merzel.sabovic@kclj.si

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Eva Klara Merzel Šabović, MD, PhD, Principal Investigator

Study Record Dates

• First Submitted: August 12, 2026
• First Posted: August 18, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): October 1, 2028
• Last Updated: August 20, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

SL (1)