Nonantibiotic Properties of Tetracyclines in Rosacea and Their Clinical Implications

James Q Del Rosso, Guy Webster, Jonathan S Weiss, Neal D Bhatia, Linda Stein Gold, Leon Kircik, James Q Del Rosso, Guy Webster, Jonathan S Weiss, Neal D Bhatia, Linda Stein Gold, Leon Kircik

Abstract

Rosacea is one of the most common inflammatory skin diseases in the United States, with a complex pathophysiology. One of the major components of the pathophysiology of rosacea is an abnormal immune detection and response to stimuli. Tetracyclines and their derivatives, including minocycline and doxycycline, have anti-inflammatory properties independent of their antibacterial activity that correlate with certain aspects of the pathophysiology, and these drugs are often used by dermatologists to treat rosacea. Biological actions of tetracyclines correlating with rosacea include anti-inflammatory and antioxidative activities, inhibitory effects on angiogenesis, and proteolysis. The objective of this review is to re-establish the current understanding of tetracyclines and their mechanism of action as they relate to the pathophysiology and treatment of rosacea for clinicians. This includes reviewing the inflammatory aspects of rosacea that correlate with the known nonantibiotic properties of tetracyclines and providing the most up-to-date clinical evidence supporting the use of tetracyclines to treat rosacea. Given the evolving and multifactorial nature of pathophysiology, this review offers clinicians a unified picture that includes research on the links between rosacea pathophysiology and clinical presentation, the nonantibiotic properties of tetracyclines that relate to pathophysiologic pathways in rosacea, and the potential for clinical application of tetracyclines in rosacea therapy.

Keywords: Tetracycline; anti-inflammatory; doxycycline; minocycline; nonantibiotic; pathophysiology; rosacea.

Conflict of interest statement

DISCLOSURES: Dr. Del Rosso has served as a consultant (C), research investigator (RI), and/or speaker (S) for Vyne Therapeutics (C, RI, S), Almirall (C,RI, S), Bausch Health (C, RI, S), BiopharmX (C, S), Galderma (C, RI, S), JEM Health (C), Leo Pharma (C, RI, S), Mayne Pharma (C, S), Novan (C), and Sun Pharma (C,RI,S). Dr. Webster has served as a consultant for VYNE Therapeutics. Dr. Weiss is a speaker for AbbVie, Almirall, Ortho Dermatologics, Regeneron, Sanofi Genzyme; a consultant for Aclaris Therapeutics Inc. and LEO Pharma; an advisor for Dr. Reddy, VYNE Therapeutics Inc., Galderma Laboratories, LP, UCB, Valeant Pharmaceuticals International; and an investigator for AbbVie, Aclaris Therapeutics Inc., Celgene Corporation, Endo International Plc, VYNE Therapeutics Inc., Galderma, LEO Pharma, Moberg Pharma North America LLC, Novartis, Promius Pharma, LLC, and Valeant Pharmaceuticals International. Dr. Bhatia is an investigator and consultant for VYNE Therapeutics. Dr. Stein Gold is an advisor and investigator for VYNE Therapeutics Inc., Galderma, LEO Pharma, Novartis, and Valeant and is an investigator for Janssen, AbbVie, and Solgel. Dr. Kircik is an investigator and consultant for VYNE Therapeutics Inc.

Copyright © 2021. Matrix Medical Communications. All rights reserved.

Figures

FIGURE 1.
FIGURE 1.
Pathophysiology of rosacea and the role of immune dysfunction,,,,,,,,–

References

    1. Del Rosso JQ, Tanghetti E, Webster G, Stein Gold L, Thiboutot D, Gallo RL. Update on the management of rosacea from the American Acne & Rosacea Society (AARS). J Clin Aesthet Dermatol. 2019;12(6):17–24.
    1. Thiboutot D, Anderson R, Cook-Bolden F et al. Standard management options for rosacea: the 2019 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2020;82(6):1501–1510.
    1. Li WQ, Cho E, Khalili H, Wu S, Chan AT, Qureshi AA. Rosacea, use of tetracycline, and risk of incident inflammatory bowel disease in women. Clin Gastroenterol Hepatol. 2016;14(2):220–225. e221–223.
    1. Al-Dabagh A, Davis SA, McMichael AJ, Feldman SR. Rosacea in skin of color: not a rare diagnosis. Dermatol Online J. 2014;20(10) 13030/qt13031mv13039r13030ss.
    1. Tan J, Schofer H, Araviiskaia E et al. Prevalence of rosacea in the general population of Germany and Russia—the RISE study. J Eur Acad Dermatol Venereol. 2016;30(3):428–434.
    1. Ahn CS, Huang WW. Rosacea pathogenesis. Dermatol Clin. 2018;36(2):81–86.
    1. Two AM, Wu W, Gallo RL, Hata TR. Rosacea: part I. Introduction, categorization, histology, pathogenesis, and risk factors. J Am Acad Dermatol. 2015;72(5):749–758. quiz 759–760.
    1. Gallo RL, Granstein RD, Kang S et al. Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78(1):148–155.
    1. van Zuuren EJ, Fedorowicz Z, Tan J et al. Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments. Br J Dermatol. 2019;181(1):65–79.
    1. Buddenkotte J, Steinhoff M. Recent advances in understanding and managing rosacea. F1000Res. 2018;7 F100 Faculty Rev-1885.
    1. National Rosacea Society. Rosacea triggers survey. Available at: Accessed January 19, 2021.
    1. Aldrich N, Gerstenblith M, Fu P et al. Genetic vs environmental factors that correlate with rosacea: a cohort-based survey of twins. JAMA Dermatol. 2015;151(11):1213–1219.
    1. Chang ALS, Raber I, Xu J et al. Assessment of the genetic basis of rosacea by genome-wide association study. J Invest Dermatol. 2015;135(6):1548–1555.
    1. Del Rosso JQ, Gallo RL, Kircik L et al. Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin. J Drugs Dermatol. 2012;11(6):694–700.
    1. Del Rosso JQ, Thiboutot D, Gallo R et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93(1):18–28.
    1. Steinhoff M, Buddenkotte J, Aubert J et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):2–11.
    1. Schwab VD, Sulk M, Seeliger S et al. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):53–62.
    1. Seeliger S, Buddenkotte J, Schmidt-Choudhury A et al. Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in vivo. Am J Pathol. 2010;177(5):2563–2575.
    1. Sulk M, Seeliger S, Aubert J et al. Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J Invest Dermatol. 2012;132(4):1253–1262.
    1. Wladis EJ, Iglesias BV, Adam AP, Gosselin EJ. Molecular biologic assessment of cutaneous specimens of ocular rosacea. Ophthalmic Plast Reconstr Surg. 2012;28(4):246–250.
    1. Garrido-Mesa N, Zarzuelo A, Gálvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169(2):337–352.
    1. Garrido-Mesa N, Zarzuelo A, Gálvez J. What is behind the non-antibiotic properties of minocycline? Pharmacol Res. 2013;67(1):18–30.
    1. Monk E, Shalita A, Siegel DM. Clinical applications of non-antimicrobial tetracyclines in dermatology. Pharmacol Res. 2011;63(2):130–145.
    1. Rainer BM, Kang S, Chien AL. Rosacea: epidemiology, pathogenesis, and treatment. Dermatoendocrinol. 2017;9(1):e1361574.
    1. Ellis SR, Nguyen M, Vaughn AR et al. The skin and gut microbiome and its role in common dermatologic conditions. Microorganisms. 2019;7(11):550.
    1. McMahon F, Banville N, Bergin DA et al. Activation of neutrophils via IP3 pathway following exposure to Demodex-associated bacterial proteins. Inflammation. 2016;39(1):425–433.
    1. Kulkarni NN, Takahashi T, Sanford JA et al. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression. J Invest Dermatol. 2020;140(3):645–655. e646.
    1. Yamasaki K, Gallo RL. Rosacea as a disease of cathelicidins and skin innate immunity. J Investig Dermatol Symp Proc. 2011;15(1):12–15.
    1. Yamasaki K, Kanada K, Macleod DT et al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J Invest Dermatol. 2011;131(3):688–697.
    1. Chang YS, Huang YC. Role of Demodex mite infestation in rosacea: a systematic review and meta-analysis. J Am Acad Dermatol. 2017;77(3):441–447. e446.
    1. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54(2):258–265.
    1. Kanada KN, Nakatsuji T, Gallo RL. Doxycycline indirectly inhibits proteolytic activation of tryptic kallikrein-related peptidases and activation of cathelicidin. J Invest Dermatol. 2012;132(5):1435–1442.
    1. Buhl T, Sulk M, Nowak P et al. Molecular and morphological characterization of inflammatory Iinfiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol. 2015;135(9):2198–2208.
    1. Yamasaki K, Di Nardo A, Bardan A et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975–980.
    1. Muto Y, Wang Z, Vanderberghe M et al. Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol. 2014;134(11):2728–2736.
    1. Hachem JP, Houben E, Crumrine D et al. Serine protease signaling of epidermal permeability barrier homeostasis. J Invest Dermatol. 2006;126(9):2074–2086.
    1. Raghallaigh SN, Powell FC. Epidermal hydration levels in patients with rosacea improve after minocycline therapy. Br J Dermatol. 2014;171(2):259–266.
    1. Koczulla R, von Degenfeld G, Kupatt C et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111(11):1665–1672.
    1. Parenti A, Indorato B, Paccosi S. Minocycline affects human neutrophil respiratory burst and transendothelial migration. Inflamm Res. 2017;66(2):107–109.
    1. Erdogan HK, Bulur I, Kocaturk E et al. Advanced oxidation protein products and serum total oxidant/antioxidant status levels in rosacea. Postepy Dermatol Alergol. 2018;35(3):304–308.
    1. Braff MH, Hawkins MA, Di Nardo A et al. Structure-function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities. J Immunol. 2005;174(7):4271–4278.
    1. Yamasaki K, Schauber J, Coda A et al. Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J. 2006;20(12):2068–2080.
    1. Reinholz M, Ruzicka T, Schauber J. Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann Dermatol. 2012;24(2):126–135.
    1. Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. 2009;55(2):77–81.
    1. Maatta M, Kari O, Tervahartiala T et al. Tear fluid levels of MMP-8 are elevated in ocular rosacea—treatment effect of oral doxycycline. Graefes Arch Clin Exp Ophthalmol. 2006;244(8):957–962.
    1. Afonso AA, Sobrin L, Monroy DC et al. Tear fluid gelatinase B activity correlates with IL-1alpha concentration and fluorescein clearance in ocular rosacea. Invest Ophthalmol Vis Sci. 1999;40(11):2506–2512.
    1. Jung SK, Lee KW, Kim HY et al. Myricetin suppresses UVB-induced wrinkle formation and MMP-9 expression by inhibiting Raf. Biochem Pharmacol. 2010;79(10):1455–1461.
    1. Cui N, Hu M, Khalil RA. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci. 2017;147:1–73.
    1. Lam-Franco L, Perfecto-Avalos Y, Patiño-Ramírez BE, Rodríguez García A. IL-1α and MMP-9 tear levels of patients with active ocular rosacea before and after treatment with systemic azithromycin or doxycycline. Ophthalmic Res. 2018;60(2):109–114.
    1. Zaenglein AL, Pathy AL, Schlosser BJ et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945–973. e933.
    1. Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007;25(2):133–135. v.
    1. Garner SE, Eady A, Bennett C, Newton JN, Thomas K, Popescu CM. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev. 2012;(8):CD002086.
    1. Ochsendorf F. Minocycline in acne vulgaris: benefits and risks. Am J Clin Dermatol. 2010;11(5):327–341.
    1. Raoof TJ, Hooper D, Moore A et al. Efficacy and safety of a novel topical minocycline foam for the treatment of moderate to severe acne vulgaris: a phase 3 study. J Am Acad Dermatol. 2020;82(4):832–837.
    1. Sutcliffe J, McLaughlin R, Webster G et al. Susceptibility of Cutibacterium acnes to topical minocycline foam. Anaerobe. 2020;62:102169.
    1. Furlong-Silva J, Cross SD, Marriott AE et al. Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis. J Clin Invest. 2021;131(5):140853.
    1. Kim Y, Kim J, Lee H et al. Tetracycline analogs inhibit osteoclast differentiation by suppressing MMP-9-mediated histone H3 cleavage. Int J Mol Sci. 2019;20(16):4038.
    1. Nakagawa T, Kakizoe Y, Iwata Y et al. Doxycycline attenuates cisplatin-induced acute kidney injury through pleiotropic effects. Am J Physiol Renal Physiol. 2018;315(5):F1347–F1357.
    1. Vellimana AK, Zhou ML, Singh I et al. Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase-9 inhibition. Ann Clin Transl Neurol. 2017;4(12):865–876.
    1. Webster GF, Toso SM, Hegemann L. Inhibition of a model of in vitro granuloma formation by tetracyclines and ciprofloxacin. Involvement of protein kinase C. Arch Dermatol. 1994;130(6):748–752.
    1. Di Nardo A, Holmes AD, Muto Y et al. Improved clinical outcome and biomarkers in adults with papulopustular rosacea treated with doxycycline modified-release capsules in a randomized trial. J Am Acad Dermatol. 2016;74(6):1086–1092.
    1. Bevins CL, Liu FT. Rosacea: skin innate immunity gone awry? Nat Med. 2007;13(8):904–906.
    1. Esterly NB, Furey NL, Flanagan LE. The effect of antimicrobial agents on leukocyte chemotaxis. J Invest Dermatol. 1978;70(1):51–55.
    1. Esterly NB, Koransky JS, Furey NL, Trevisan M. Neutrophil chemotaxis in patients with acne receiving oral tetracycline therapy. Arch Dermatol. 1984;120(10):1308–1313.
    1. Takeshita S, Ono Y, Kozuma K et al. Modulation of oxidative burst of neutrophils by doxycycline in patients with acute myocardial infarction. J Antimicrob Chemother. 2002;49(2):411–413.
    1. Hanemaaijer R, Visser H, Koolwijk P et al. Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res. 1998;12(2):114–118.
    1. Guimaraes DA, Rizzi E, Ceron CS et al. Doxycycline dose-dependently inhibits MMP-2-mediated vascular changes in 2K1C hypertension. Basic Clin Pharmacol Toxicol. 2011;108(5):318–325.
    1. Golub LM, Lee HM, Lehrer G et al. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res. 1983;18(5):516–526.
    1. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain. 2002;125:1297–1308. (Pt 6):
    1. Yao JS, Chen Y, Zhai W et al. Minocycline exerts multiple inhibitory effects on vascular endothelial growth factor-induced smooth muscle cell migration: the role of ERK1/2, PI3K, and matrix metalloproteinases. Circ Res. 2004;95(4):364–371.
    1. Machado LS, Kozak A, Ergul A et al. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006;7:56.
    1. Ali S, Driscoll HE, Newton VL, Gardiner NJ. Matrix metalloproteinase-2 is downregulated in sciatic nerve by streptozotocin induced diabetes and/or treatment with minocycline: implications for nerve regeneration. Exp Neurol. 2014;261:654–665.
    1. Tamargo RJ, Bok RA, Brem H. Angiogenesis inhibition by minocycline. Cancer Res. 1991;51(2):672–675.
    1. Yao JS, Shen F, Young WL, Yang GY. Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int. 2007;50(3):524–530.
    1. Guerra AD, Rose WE, Hematti P, Kao WJ. Minocycline modulates NFĸB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells. Stem Cell Res Ther. 2017;8(1):171.
    1. Golub LM, Lee HM, Ryan ME et al. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res. 1998;12(2):12–26.
    1. Masumori N, Tsukamoto T, Miyao N et al. Inhibitory effect of minocycline on in vitro invasion and experimental metastasis of mouse renal adenocarcinoma. J Urol. 1994;151(5):1400–1404.
    1. Li DQ, Chen Z, Song XJ, Luo L, Pflugfelder SC. Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2004;45(12):4302–4311.
    1. Uitto VJ, Firth JD, Nip L, Golub LM. Doxycycline and chemically modified tetracyclines inhibit gelatinase A (MMP-2) gene expression in human skin keratinocytes. Ann N Y Acad Sci. 1994;732:140–151.
    1. Quarterman MJ, Johnson DW, Abele DC et al. Ocular rosacea. Signs, symptoms, and tear studies before and after treatment with doxycycline. Arch Dermatol. 1997;133(1):49–54.
    1. Ta CN, Shine WE, McCulley JP et al. Effects of minocycline on the ocular flora of patients with acne rosacea or seborrheic blepharitis. Cornea. 2003;22(6):545–548.
    1. Del Rosso JQ, Webster GF, Jackson M et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791–802.
    1. Fowler JF., Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, usp monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6(6):641–645.
    1. Oracea [prescribing information]. Fort Worth, TX: Galderma Laboratories, LP; December 2014.
    1. Jackson JM, Kircik LH, Lorenz DJ. Efficacy of extended-release 45 mg oral minocycline and extended-release 45 mg oral minocycline plus 15% azelaic acid in the treatment of acne rosacea. J Drugs Dermatol. 2013;12(3):292–298.
    1. van der Linden MMD, van Ratingen AR, van Rappard DC, Nieuwenburg SA, Spuls PI. DOMINO, doxycycline 40 mg vs. minocycline 100 mg in the treatment of rosacea: a randomized, single-blinded, noninferiority trial, comparing efficacy and safety. Br J Dermatol. 2017;176(6):1465–1474.
    1. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005;27(9):1329–1342.
    1. Oge LK, Muncie HL, Phillips-Savoy AR. Rosacea: diagnosis and treatment. Am Fam Physician. 2015;92(3):187–196.
    1. Kircik L, Del Rosso JQ, Weiss JS et al. Formulation and profile of FMX101 4% minocycline topical foam for the treatment of acne vulgaris. J Clin Aesthet Dermatol. 2020;13(4):14–21.
    1. ZILXI (minocycline) topical foam, 1.5% [prescribing information]. Bridgewater, NJ: Foamix Pharmaceuticals Inc.; May 2020.
    1. Gold LS, Del Rosso JQ, Kircik L et al. Minocycline 1.5% foam for the topical treatment of moderate to severe papulopustular rosacea: results of 2 phase 3, randomized, clinical trials. J Am Acad Dermatol. 2020;82(5):1166–1173.
    1. Stein Gold L, Del Rosso JQ, Kircik L et al. Open-label extension study evaluating long-term safety and efficacy of FMX103 1.5% minocycline topical foam for the treatment of moderate-to-severe papulopustular rosacea. J Clin Aesthet Dermatol. 2020;13(11):44–49.
    1. Mrowietz U, Kedem TH, Keynan R et al. A phase II, randomized, double-blind clinical study evaluating the safety, tolerability, and efficacy of a topical minocycline foam, FMX103, for the treatment of facial papulopustular rosacea. Am J Clin Dermatol. 2018;19(3):427–436.
    1. Webster GF, Toso SM, Hegeman L: Inhibition of a model of granuloma formation by tetracyclines and ciprofloxacin: Involvement of protein kinase C. Arch Dermatol. 1994;130:748–752.

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