Reduction of Erythema in Moderate-Severe Rosacea by a Low Molecular Weight Heparan Sulfate Analog (HSA)

June 2023 | Volume 22 | Issue 6 | 546 | Copyright © June 2023


Published online May 31, 2023

Rosalyn George MDa, Richard L. Gallo MD PhDb, Joel L. Cohen MDc,d, Madeline Brown BSe, Chidubem A. V. Okeke BSf, Angel S. Byrd MD PhDg

aWilmington Dermatology Center, Wilmington, NC
bDepartment of Dermatology, University of California San Diego, La Jolla, CA
cAboutSkin Dermatology and DermSurgery, PC, Greenwood Village, CO
dDermatology, University of California, Irvine, CA
eUniversity of Maryland School of Medicine, Baltimore, MD
fHoward University College of Medicine, Washington, DC
gDepartment of Dermatology, Howard University College of Medicine, Washington, DC

Abstract
Rosacea changes are a result of an immune mediated response and the angiogenic properties of the LL-37 peptide. This peptide induces an inflammatory signal that activates the NLRP3-mediated inflammasome, triggering rosacea pathogenesis. Research findings show that LL-37 peptide is inhibited by binding to a cell surface glycosaminoglycan, heparan sulfate. Heparan Sulfate Analog (HSA) is a proprietary low molecular weight analog of heparan sulfate that has been formulated into a Dermal Repair Cream (DRC), specifically to aid in such immune mediated responses. Herein, in vitro studies using human epidermal keratinocytes showed an increase in HSA decreased LL-37 toxicity and IL-8 cytokine release. A single-center, randomized double-blind trial included 16 subjects (Fitzpatrick skin types I-IV) with a clinical diagnosis of type 1 rosacea and moderate to severe facial erythema, who were undergoing Pulsed Dye Laser (PDL) treatment. The clinical improvements of their facial erythema were assessed at baseline, 2 weeks, 4 weeks, and 8 weeks. Results revealed that low molecular weight HSA significantly improves the clinical signs of rosacea during the 8 weeks of use likely resulting from inhibition of LL-37 induced IL-8 cytokine release. These findings support the use of DRC in rosacea topical treatment regimens as it demonstrates visible skin benefits and improves tolerability of PDL therapy in a shorter duration of time as compared with PDL alone.

George R, Gallo RL, Cohen JL, et al. Reduction of erythema in moderate-severe rosacea by a low molecular weight Heparan Sulfate Analog (HSA). J Drugs Dermatol. 2023;22(6):546-553. doi:10.36849/JDD.7494

INTRODUCTION

Rosacea is a chronic inflammatory skin condition that affects blood vessels and pilosebaceous units.1 It is characterized by recurrent flushing, telangiectasia, central facial erythema, and papules/pustules that often present on the nose, cheek, forehead, and chin.2,3 The clinical signs and symptoms of rosacea vary but may include redness, dryness, edema, and stinging/burning.3 Rosacea can have a massive impact on patients' quality of life as those with the condition report experiencing increased anxiety, depression, and embarrassment.4-6 Despite its high burden, the choice of treatment is still challenging. The National Rosacea Society Expert Committee, American Academy of Dermatology, and National Institute of Arthritis and Musculoskeletal and Skin Diseases recommend standard management options which include topical/oral medications and laser/surgical interventions. A study by Baldwin et al7 has shown that other over-the-counter (OTC) skin care products such as IL-8, cleansers, moisturizers, and sunscreen remain instrumental in rosacea therapy.

Although retinoids are recommended for phymatous rosacea, there is a lack of OTC products to tackle the persistent facial redness many patients experience. This highlights a significant need for an efficacious, nonpharmacological treatment for the facial erythema of rosacea that can be integrated seamlessly into patients’ treatment skincare regimens.

Research suggests that rosacea's various phenotypes are a result of an immune mediated response as well as the angiogenic properties of the antimicrobial peptide LL-37, which has a high prevalence and expression level in rosacea patients.8 When bound to lipopolysaccharides (LPS) found in bacteria,  LL-37 induces an inflammatory signal cascade that activates the NLRP3-mediated inflammasome, triggering skin inflammation, new blood vessel growth, and rosacea pathogenesis.9  LL-37 also induces the secretion of Th1-inducing cytokines, IL-8, generation of reactive oxygen species, and inhibition of bacterial growth. This results in a disruption of the skin barrier function which consequently enhances the entry of foreign
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