COMMENTARY
Rosacea and cardiovascular disease: Is there an association? Jacquelyn Dosal, MD, and Jonette Keri, MD, PhD Miami, Florida See related article on page 249 Key words: antibiotics; cardiovascular disease; rosacea; tetracyclines.
ver the past decade, emerging evidence has compellingly linked psoriasis to cardiovascular disease (CVD).1 Similarly, recently published data link treatment of rosacea using oral tetracyclines to a reduced risk of vascular events.2 The results suggest that opportunities exist to holistically treat patients with rosacea. Patients with a severe type of rosacea, such as rosacea fulminans, may show obvious signs of systemic inflammation such as low-grade fever and elevated white cell count and erythrocyte sedimentation rate. Conversely, the more common types of rosacea (erythematotelangiectatic, papulopustular, phymatous, and ocular) do not show such overt signs of inflammation, however it is possible that subclinical systemic inflammation exists in other organ systems. It is already known that high total cholesterol, low-density lipoprotein, and C-reactive protein; a family history of premature CVD; and a history of smoking and alcohol consumption have been found to be significantly more common in patients with rosacea compared with control subjects.3 In a large retrospective review,2 it was found that treating rosacea with an oral tetracycline lowered the incidence of vascular events. Patients with rosacea that were prescribed a tetracycline had a favorable odds ratio for the development of vascular disease compared with those not prescribed a tetracycline (odds ratio 0.69 in the univariate model, 95% confidence interval 0.61-0.79, P \ .05; odds ratio 0.78 in the multivariate model, 95% confidence interval 0.68-0.89, P \.05). Although the results are preliminary and should be confirmed using
O
other patient populations, it is proposed that the anti-inflammatory properties of tetracyclines may have beneficial secondary effects on the cardiovascular system of veterans with rosacea. It is yet unclear if the observed effect was because of the direct effect of the use of a tetracycline, or improvement associated with the systemic treatment of rosacea itself. It is possible that systemically treating the rosacea may constitute a risk factor reduction, much like improving body mass index can reduce the risk of heart disease. Although it is unclear how tetracyclines may benefit the cardiovascular system, matrix metalloproteinases (MMPs) are influential in the pathology of both rosacea and CVD. Tetracyclines inhibit MMP activity, therefore it would follow that treating one disease may have benefits on both organ systems. MMP-2 and MMP-9, both of which tetracyclines inhibit, are enzymes that degrade the basement membrane of capillaries. Doxycycline has been shown to defend capillary wall and connective tissue integrity, reduce hypersensitivity to vasodilatory stimuli, prevent leakage of capillaries, and inhibit cytokines involved in inflammation and erythema, all of which is seen in rosacea.4 There are also data that 90-day subantimicrobial-dose doxycycline lowers serum C-reactive protein over a 2-year period in postmenopausal women.5 Although there are limitations to retrospective reviews, the data by Dosal et al2 do raise some questions about how we should approach our patients with rosacea, especially in a current clinical environment where systemic treatment of rosacea is under scrutiny for bacterial resistance concerns.
From the Department of Dermatology and Cutaneous Surgery, University of Miami. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Jacquelyn Dosal, MD, Department of Dermatology and Cutaneous Surgery, University of Miami, 1600 NW 10th Ave, RMSB 2023A, Miami, FL 3313. E-mail: [email protected]. edu.
J Am Acad Dermatol 2015;73:308-9. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. Published by Elsevier. All rights reserved. http://dx.doi.org/10.1016/j.jaad.2015.03.031
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J AM ACAD DERMATOL VOLUME 73, NUMBER 2
Previous studies support the idea of antibiotics influencing CVD.6 In a study by Meier et al6 in 1999, patients who were treated for an infection with tetracyclines showed a statistically significant reduction in their incidence of acute myocardial infarction, whereas other antibiotics did not show this effect. The authors believe that the observed effect is because of tetracyclines’ distinct nonantibacterial mechanisms such as MMP inhibition and suppression of inflammatory mediators that protects vulnerable atherosclerotic plaques from rupture, thereby protecting from cardiac events.6 Systemic inflammation often bridges the gap between cutaneous disease and internal disease. The treatment of rosacea may have systemic implications and impact patient outcomes.2 We suggest the following hypotheses deserve more attention and research: 1. Patients with rosacea should be checked for other cardiovascular risk factors and addressed, if present. 2. Rosacea is an independent risk factor for CVD. 3. Treatment for rosacea should be aimed at both skin and systemic outcomes. For primary prevention of heart disease, 81 mg of aspirin is often recommended, especially in patients with important or several risk factors. Similarly, is it possible that there may be a beneficial effect of low-dose tetracycline (a subantimicrobial dose that preserves anti-inflammatory activity) as a mechanism to decrease the activity of MMPs and another extracellular matrix destabilizing enzymes, with the hopes of preventing vascular disease/events? Clinical trials would be needed to demonstrate
Dosal and Keri 309
clinical benefit, but a rationale exists and early retrospective reviews are promising. With less concern for antibiotic resistance,7 the use of submicrobial-dose tetracyclines may represent a relatively safe primary prevention measure. Beyond the normal cardiovascular metabolic risk factors, systemic treatment of rosacea may represent another important modifiable risk factor for primary prevention of vascular disease. The authors would like to thank Dr Robert Kirsner for his mentorship and encouragement. REFERENCES 1. Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009;145(6):700-703. 2. Dosal JR, Rodriguez GL, Penzon CF, Li H, Keri JE. Effect of tetracyclines on the development of vascular disease in veterans with acne or rosacea: a retrospective cohort study. J Invest Dermatol. 2014;134(8):2267-2269. 3. Duman N, Ersoy Evans S, Atakan N. Rosacea and cardiovascular risk factors: a case control study. J Eur Acad Dermatol Venereol. 2014;28:1165-1169. 4. Bender A, Zapolanski T, Watkins S, et al. Tetracycline suppresses ATPgS-induced CXCL8 and CXCL1 production by the human dermal microvascular endothelial cell-1 (HMEC-1) cell line and primary human dermal microvascular endothelial cells. Exp Dermatol. 2008;17(9):752-760. 5. Koppikar RS, Agrawal SV. The effect of sub-antimicrobial dose-doxycycline periodontal therapy on serum inflammatory biomarker C-reactive protein levels in post-menopausal women: a 2-year, double-blinded, randomized clinical trial. Contemp Clin Dent. 2013;4(1):71-73. 6. Meier CR, Derby LE, Jick SS, Vasilakis C, Jick H. Antibiotics and risk of subsequent first-time acute myocardial infarction. JAMA. 1999;281(5):427431. 7. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464.
Rosacea and cardiovascular disease: Is there an association? Jacquelyn Dosal, MD, and Jonette Keri, MD, PhD Miami, Florida See related article on page 249 Key words: antibiotics; cardiovascular disease; rosacea; tetracyclines.
ver the past decade, emerging evidence has compellingly linked psoriasis to cardiovascular disease (CVD).1 Similarly, recently published data link treatment of rosacea using oral tetracyclines to a reduced risk of vascular events.2 The results suggest that opportunities exist to holistically treat patients with rosacea. Patients with a severe type of rosacea, such as rosacea fulminans, may show obvious signs of systemic inflammation such as low-grade fever and elevated white cell count and erythrocyte sedimentation rate. Conversely, the more common types of rosacea (erythematotelangiectatic, papulopustular, phymatous, and ocular) do not show such overt signs of inflammation, however it is possible that subclinical systemic inflammation exists in other organ systems. It is already known that high total cholesterol, low-density lipoprotein, and C-reactive protein; a family history of premature CVD; and a history of smoking and alcohol consumption have been found to be significantly more common in patients with rosacea compared with control subjects.3 In a large retrospective review,2 it was found that treating rosacea with an oral tetracycline lowered the incidence of vascular events. Patients with rosacea that were prescribed a tetracycline had a favorable odds ratio for the development of vascular disease compared with those not prescribed a tetracycline (odds ratio 0.69 in the univariate model, 95% confidence interval 0.61-0.79, P \ .05; odds ratio 0.78 in the multivariate model, 95% confidence interval 0.68-0.89, P \.05). Although the results are preliminary and should be confirmed using
O
other patient populations, it is proposed that the anti-inflammatory properties of tetracyclines may have beneficial secondary effects on the cardiovascular system of veterans with rosacea. It is yet unclear if the observed effect was because of the direct effect of the use of a tetracycline, or improvement associated with the systemic treatment of rosacea itself. It is possible that systemically treating the rosacea may constitute a risk factor reduction, much like improving body mass index can reduce the risk of heart disease. Although it is unclear how tetracyclines may benefit the cardiovascular system, matrix metalloproteinases (MMPs) are influential in the pathology of both rosacea and CVD. Tetracyclines inhibit MMP activity, therefore it would follow that treating one disease may have benefits on both organ systems. MMP-2 and MMP-9, both of which tetracyclines inhibit, are enzymes that degrade the basement membrane of capillaries. Doxycycline has been shown to defend capillary wall and connective tissue integrity, reduce hypersensitivity to vasodilatory stimuli, prevent leakage of capillaries, and inhibit cytokines involved in inflammation and erythema, all of which is seen in rosacea.4 There are also data that 90-day subantimicrobial-dose doxycycline lowers serum C-reactive protein over a 2-year period in postmenopausal women.5 Although there are limitations to retrospective reviews, the data by Dosal et al2 do raise some questions about how we should approach our patients with rosacea, especially in a current clinical environment where systemic treatment of rosacea is under scrutiny for bacterial resistance concerns.
From the Department of Dermatology and Cutaneous Surgery, University of Miami. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Jacquelyn Dosal, MD, Department of Dermatology and Cutaneous Surgery, University of Miami, 1600 NW 10th Ave, RMSB 2023A, Miami, FL 3313. E-mail: [email protected]. edu.
J Am Acad Dermatol 2015;73:308-9. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. Published by Elsevier. All rights reserved. http://dx.doi.org/10.1016/j.jaad.2015.03.031
308
J AM ACAD DERMATOL VOLUME 73, NUMBER 2
Previous studies support the idea of antibiotics influencing CVD.6 In a study by Meier et al6 in 1999, patients who were treated for an infection with tetracyclines showed a statistically significant reduction in their incidence of acute myocardial infarction, whereas other antibiotics did not show this effect. The authors believe that the observed effect is because of tetracyclines’ distinct nonantibacterial mechanisms such as MMP inhibition and suppression of inflammatory mediators that protects vulnerable atherosclerotic plaques from rupture, thereby protecting from cardiac events.6 Systemic inflammation often bridges the gap between cutaneous disease and internal disease. The treatment of rosacea may have systemic implications and impact patient outcomes.2 We suggest the following hypotheses deserve more attention and research: 1. Patients with rosacea should be checked for other cardiovascular risk factors and addressed, if present. 2. Rosacea is an independent risk factor for CVD. 3. Treatment for rosacea should be aimed at both skin and systemic outcomes. For primary prevention of heart disease, 81 mg of aspirin is often recommended, especially in patients with important or several risk factors. Similarly, is it possible that there may be a beneficial effect of low-dose tetracycline (a subantimicrobial dose that preserves anti-inflammatory activity) as a mechanism to decrease the activity of MMPs and another extracellular matrix destabilizing enzymes, with the hopes of preventing vascular disease/events? Clinical trials would be needed to demonstrate
Dosal and Keri 309
clinical benefit, but a rationale exists and early retrospective reviews are promising. With less concern for antibiotic resistance,7 the use of submicrobial-dose tetracyclines may represent a relatively safe primary prevention measure. Beyond the normal cardiovascular metabolic risk factors, systemic treatment of rosacea may represent another important modifiable risk factor for primary prevention of vascular disease. The authors would like to thank Dr Robert Kirsner for his mentorship and encouragement. REFERENCES 1. Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009;145(6):700-703. 2. Dosal JR, Rodriguez GL, Penzon CF, Li H, Keri JE. Effect of tetracyclines on the development of vascular disease in veterans with acne or rosacea: a retrospective cohort study. J Invest Dermatol. 2014;134(8):2267-2269. 3. Duman N, Ersoy Evans S, Atakan N. Rosacea and cardiovascular risk factors: a case control study. J Eur Acad Dermatol Venereol. 2014;28:1165-1169. 4. Bender A, Zapolanski T, Watkins S, et al. Tetracycline suppresses ATPgS-induced CXCL8 and CXCL1 production by the human dermal microvascular endothelial cell-1 (HMEC-1) cell line and primary human dermal microvascular endothelial cells. Exp Dermatol. 2008;17(9):752-760. 5. Koppikar RS, Agrawal SV. The effect of sub-antimicrobial dose-doxycycline periodontal therapy on serum inflammatory biomarker C-reactive protein levels in post-menopausal women: a 2-year, double-blinded, randomized clinical trial. Contemp Clin Dent. 2013;4(1):71-73. 6. Meier CR, Derby LE, Jick SS, Vasilakis C, Jick H. Antibiotics and risk of subsequent first-time acute myocardial infarction. JAMA. 1999;281(5):427431. 7. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464.
