Increased Understanding of Rosacea Pathogenesis Leads to An Increase in Therapeutic Options

Rosacea imposes a substantial burden on both patients and the economy, and further research is needed to better understand its pathogenesis and develop new treatments, according to an article published in Frontiers in Medicine.

“Current research is continually elucidating new details about the disease and new data may indicate effective therapeutic targets,” wrote Garrett Fisher, Departments of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University in Dayton, OH, and coauthors. “Overall, as research into pathogenesis and drug discovery continues, we may generate new effective therapies for all rosacea phenotypes,” they added.

Rosacea's pathogenesis is complex and multifaceted, with primary factors including skin barrier dysfunction and environmental/genetic triggers. Known molecular players in rosacea include the cathelicidin family, transient receptor potential (TRP) channels, mast cells, and the pyrin domain-containing protein (NLRP3) inflammasome. Each component contributes to the inflammatory and phenotypic manifestations of rosacea, such as erythema, pustules, and flushing. Skin barrier dysfunction, possibly due to Demodex mites and disrupted skin homeostasis, leads to immune infiltration and inflammation. Cathelicidin, a peptide involved in innate immunity, is processed into pro-inflammatory fragments that can exacerbate rosacea symptoms through mast cell activation and inflammasome activation.

TRP channels involve sensory responses that can exacerbate rosacea symptoms like flushing and stinging. Their activation can lead to inflammatory responses characteristic of rosacea. These channels are essential for ion transport across cell membranes and are upregulated in rosacea, contributing to the disease's sensory symptoms.

Mast cells play a significant role in rosacea by responding to microbial triggers and environmental stressors through degranulation and cytokine release. This response contributes to the chronic inflammatory state observed in rosacea. The pathways involved include interactions with TLRs and the subsequent activation of inflammatory mediators.

The NLRP3 inflammasome is a key component in the inflammatory response in rosacea. It's activated by various triggers, including LL-37, leading to the release of IL-1𝛽 and IL-18. These cytokines are crucial for the inflammatory response in rosacea, contributing to symptoms like erythema and pustules.

Current therapeutics for rosacea include general measures such as cleansers, UV protection, and moisturizers to maintain the skin barrier and reduce inflammation. Topical agents like brimonidine and oxymetazoline address flushing and erythema, while ivermectin and azelaic acid focus on inflammation and microbial control in papules and pustules. Oral treatments, primarily tetracyclines such as doxycycline and minocycline, leverage their anti-inflammatory properties for papulopustular rosacea. Off-label options like isotretinoin and carvedilol are used for severe cases to inhibit sebaceous glands and stabilize mast cells. Future therapies explore targeting skin barrier dysfunction with Janus kinase (JAK) and signal transducer and activator of transcription (STAT) inhibitors, the cathelicidin pathway with mammalian target of rapamycin (mTOR) inhibitors, and mast cell pathways with treatments like hydroxychloroquine and G-protein-coupled receptors (GPCR) modulators. Additionally, emerging treatments aim to inhibit microvesicle particle production with antidepressants and selective serotonin reuptake inhibitors (SSRIs) to mitigate erythema and inflammation, reflecting rosacea treatment's dynamic and evolving landscape.

“Overall, recent studies have provided important insights and targets in rosacea,” concluded the study authors. “As further pathogenic insights are developed more effective therapies will become available,” they added.

Reference

Fisher GW, Travers JB, Rohan CA. Rosacea pathogenesis and therapeutics: current treatments and a look at future targets. Front Med (Lausanne). 2023;10:1292722. doi:10.3389/fmed.2023.1292722