Cathelicidin, kallikrein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel

Abstract

Background Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea. Objective We sought to evaluate the effects of azelaic acid (AzA) on these elements of the innate immune system. Methods Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel. Results AzA directly inhibited KLK5 in cultured keratinocytes and gene expression of KLK5, Toll-like receptor-2, and cathelicidin in mouse skin. Patients with rosacea showed reduction in cathelicidin and KLK5 messenger RNA after treatment with AzA gel. Subjects without rosacea had lower serine protease activity (SPA) than patients with rosacea. Distinct subsets of patients with rosacea who had high and low baseline SPA were identified, and patients with high baseline exhibited a statistically significant reduction of SPA with 15% AzA gel treatment. Limitations Study size was insufficient to predict clinical efficacy based on the innate immune response to AzA. Conclusions These results show that cathelicidin and KLK5 decrease in association with AZA exposure. Our observations suggest a new mechanism of action for AzA and that SPA may be a useful biomarker for disease activity.

Antibiotic Resistance Considerations of Importance to Clinical Dermatologists

“…[30][31][32][33][34] As a result, many of the studies of therapies used to treat rosacea (eg tetracyclines, azelaic acid, ivermectin) especially with presence of papulopustular lesions, appear to affect inflammatory pathways/modes of action unrelated to an underlying bacterial trigger that appear to be operative in rosacea pathophysiology (eg inhibition of matrix metalloproteinases, downregulation of cathelicidin pathway, reduction in number of Demodex mites). [35][36][37][38][39][40][41][42][43] The large body of evidence supporting an inflammatory pathogenesis of rosacea that is not triggered by a bacterial etiology has led globally to rosacea management recommendations supporting that avoidance of an antibiotic effect whenever possible is favorable in order to reduce the emergence of antibiotic-resistant bacteria. [44][45][46][47] In their rosacea medical management guidelines, the American Acne & Rosacea Society stated the following: "The lack of data supporting a bacterial component definitively related to the pathogenesis of rosacea suggests overall that medical therapies which are anti-inflammatory in nature are best considered for initial treatment of rosacea, especially the inflammatory (papulopustular) subtype, with oral antibiotic agents used in cases that are poorly responsive to a reasonable trial of topical therapy and/or oral anti-inflammatory therapy".…”

“…44 To achieve this, available topical agents with demonstrated anti-inflammatory effects, efficacy, and safety in rosacea would include azelaic acid and ivermectin. 41,42,[44][45][46][47][48][49] Sub-antibiotic dose doxycycline (such as the modified-release 40 mg capsule once daily or 20 mg immediate-release tablet twice daily) provides anti-inflammatory effects with efficacy and favorable safety for rosacea, without inducing antibiotic selection pressure. 40,[44][45][46][47]50 …”

Rosacea – new data on pathogenesis and treatment

“…Angiogenny wpływ mają rów-nież katelicydyny oraz serynowe proteazy kallikreiny 5. Ekspresja genów tych białek jest hamowana między innymi podczas leczenia 15% kwasem azelainowym [16].…”

“…Takie stanowisko przedstawiono też w konsensusie na temat leczenia rosacea [1]. Wyjątek stanowi retinaldehyd, który przy słabszym działaniu przeciwzapalnym powoduje jednak o wiele mniejsze podrażnienia i może być w niektórych przypadkach korzystny dla skóry w rosacea [16], co potwierdzili w badaniu Kałużna i Placek [52,53].…”

Current Drug Therapies for Rosacea: A Chronic Vascular and Inflammatory Skin Disease

“…53,[61][62][63][64][65][66] Azelaic acid downregulates cathelicidins by inhibiting serine protease KLK5 activity. 67,68 The most common treatment-related adverse events reported in 12-week and 15-week clinical trials were burning/ stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%), and erythema/irritation (4%). 69 Another topical medication approved by the FDA and recommended by the AARS for the treatment of rosacea is sodium sulfacetamide 10%-sulfur 5%.…”