Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema

Abstract

Background: Lymphedema is a common condition affecting millions around the world that still lacks approved medical therapy. Because ketoprofen, an NSAID, has been therapeutic in experimental lymphedema, we evaluated its efficacy in humans.

Methods: We first performed an exploratory open-label trial. Patients with either primary or secondary lymphedema received ketoprofen 75 mg by mouth 3 times daily for 4 months. Subjects were evaluated for changes in histopathology, with skin thickness, limb volume, and tissue bioimpedance changes serving as secondary endpoints. Based on our encouraging findings, we next conducted a placebo-controlled trial, with the primary outcome defined as a change in skin thickness, as measured by skin calipers. Secondary endpoints for this second study included histopathology, limb volume, bioimpedance, and systemic inflammatory mediators.

Results: We enrolled 21 lymphedema patients in the open-label trial, from November 2010 to July 2011. Histopathology and skin thickness were significantly improved at 4 months compared with baseline. In the follow-up, double-blind, placebo-controlled trial, we enrolled 34 patients from August 2011 to October 2015, with 16 ketoprofen recipients and 18 placebo-treated subjects. No serious adverse events occurred. The ketoprofen recipients demonstrated reduced skin thickness, as well as improved composite measures of histopathology and decreased plasma granulocyte CSF (G-CSF) expression.

Conclusion: These 2 exploratory studies together support the utility of targeted antiinflammatory therapy with ketoprofen in patients with lymphedema. Our results highlight the promise of such approaches to help restore a failing lymphatic circulation.

Trial registration: ClinicalTrials.gov NCT02257970.

Keywords: Cardiovascular disease; Eicosanoids; Inflammation; Lymph; Vascular Biology.

Conflict of interest statement

Conflict of interest: MRN is a consultant and share-holder for Eiger Biopharmaceuticals, a company evaluating LTB4 antagonism as a treatment for lymphedema.

Figures

Figure 1. Overview of patient flow and disposition in the open-label and placebo-controlled trials.

Figure 2. Ketoprofen improves cutaneous pathology and skin thickness in open-label study.

(A) In the open-label trial, a 6-mm cutaneous punch biopsy was performed before and after ketoprofen therapy. The cutaneous histopathology score was calculated according to the predefined parameters, as described. Violin plot of the change (Δ) represents the value of the posttreatment minus the pretreatment score; a negative score indicates improvement. (B) For the open-label study, skin thickness was measured clinically by caliper before and after a 4-month exposure to daily ketoprofen therapy (n = 16). (****P < 0.0001, ***P = 0.0006, paired t test).

Figure 3. Ketoprofen improves skin thickness and cutaneous pathology in placebo-controlled study.

(A) For the placebo-controlled trial, pre- and posttreatment skin thickness were measured for the ketoprofen (n = 14) and placebo groups (n = 15). (B) Violin plots of the changes in the blindly assessed histopathology scores. The change (Δ) represents the value of the posttreatment minus the pretreatment score. (**P = 0.01, *P = 0.03, Mann-Whitney U test.)

Figure 4. Ketoprofen treatment reduces cutaneous 5-LO expression.

Skin biopsies obtained at the conclusion of the placebo-controlled trial were stained for 5-LO cells (A), macrophages (B), and neutrophils (C), and cell counts were performed in a blinded manner. (*P = 0.02, **P = 0.001, Mann-Whitney U test). Representative cutaneous histology stained for 5-LO obtained at the conclusion of the trial in the placebo (D) and ketoprofen (E) groups (20×, and magnified insets). Red arrows indicate 5-LO–positive cells.