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Combination Therapy of Doxycycline and Topical Tacrolimus for Venous Ulcers

Combination Therapy of Doxycycline and Topical Tacrolimus for Venous Ulcers Venous ulcers are common and debilitating skin lesions that occur predominantly in the lower extremities of elderly patients. They are associated with trauma and varicose veins and are highly susceptible to contact allergies to topical antibiotics, including bacitracin. Pain and infections are major causes of morbidity in patients with venous ulcers. Multiple therapies have been attempted for venous ulceration with varying degrees of success. Recently, it has been recognized that certain subsets of ulcers are highly angiogenic and that high levels of angiogenesis may prevent optimal reepithelialization.1-3 We found that patients with recessive dystrophic epidermolysis bullosa, a deficiency of collagen type VII in which ulceration is a prominent feature, have abnormally high levels of the proangiogenic factor basic fibroblast growth factor (bFGF).2 Doxycycline, a commonly used antibiotic for acne, is an effective inhibitor of matrix metalloproteinases. Given these findings, we successfully used combination therapy of doxycycline and tacrolimus for the treatment of long-standing venous ulceration in a patient who did not tolerate compression stockings. Given our success, larger studies of this therapy are justified. Report of a Case A 71-year-old woman presented with a 6-month history of moderately painful nonhealing ulcerations on her left lower extremity. On clinical examination she was found to have several superficial ulcers ranging in size from 1 to 3 cm distributed on and near her left lateral and medial ankle. The base of the ulcers contained granulation tissue and some yellow fibrinous debris. The borders were not undermined. She had significant background erythema of her left leg and pitting edema to her knee. She also had multiple medical problems, including myelodysplastic syndrome, and she was undergoing treatment with several systemic medications, including warfarin sodium and cyclosporine. She did not respond to initial treatment, which included broad-spectrum antibiotics, limb elevation, and local wound care, and did not tolerate compression stockings. A biopsy specimen revealed dermal and cutaneous sclerosis consistent with stasis changes. There was no evidence of vasculitis or vasculopathy. At that time, she was treated with 0.1% topical tacrolimus ointment twice daily with 100 mg of doxycycline hyclate by mouth twice daily. After 2 weeks, the ulcers were markedly improved, smaller, and less painful, and at 2 months, the ulcerations were nearly completely reepithelialized (Figure 1). We have treated 2 other patients with long-standing (>1 year) venous ulceration and have noted similar results. Figure 1. View LargeDownload Before and after photographs of a patient with venous ulcers. A, Venous ulceration on the patient’s leg prior to treatment. B, Patient’s leg after 2 months of combination therapy with doxycycline hyclate and 0.1% topical tacrolimus. Comment Venous ulcers are a common cause of morbidity, especially in the elderly. Multiple factors are associated with venous ulcers, including dependency, varicose veins, contact allergy to topical products, bacterial colonization, and impaired barrier function (Figure 2).4,5 Multiple therapies have been used for the treatment of venous ulceration, including grafting, topical growth factors, and hyperbaric oxygen. These therapies are very expensive and not universally effective. Figure 2. View LargeDownload A model of venous ulceration. Impaired barrier function is associated with increased synthesis and release of angiogenic growth factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The bed of the ulcer is colonized with bacteria, leading to activation of proinflammatory toll receptors (TLR2 and TLR4). Neutrophils and other mononuclear cells release proangiogenic interleukin 8 (IL-8) and matrix metalloproteinases (MMPs). The proinflammatory and highly angiogenic environment causes inhibition of reepithelialization, resulting in persistence of venous ulceration. Recently, it has been recognized that a subset of ulcers, including venous ulcers, are highly angiogenic. Increased angiogenesis is associated with the failure of epithelialization, which is often noted in cutaneous hemangiomas and neoplasms. Thus, the increased angiogenesis associated with venous ulcers may be the cause of the failure to epithelialize. We report a case that responded to the combination of topical tacrolimus and oral doxycycline. Larger studies are warranted to determine whether this simple mode of treatment should be used as first-line therapy for venous ulcers. Back to top Article Information Correspondence: Dr Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Dr, Atlanta, GA 30322 (jarbise@emory.edu). Financial Disclosure: None. Funding/Support: This work was supported by Emory Skin Disease Research Core Center grants RO1 AR47901and P30 AR42687 (Dr Arbiser) from the National Institutes of Health, Bethesda, Md. References 1. Arbiser JL Angiogenesis and the skin: a primer J Am Acad Dermatol 1996;34486- 497PubMedGoogle ScholarCrossref 2. Arbiser JLFine JDMurrell D et al. Basic fibroblast growth factor: a missing link between collagen VII, increased collagenase, and squamous cell carcinoma in recessive dystrophic epidermolysis bullosa Mol Med 1998;4191- 195PubMedGoogle Scholar 3. Arbiser JLJohnson DCohen CBrown LF High-level expression of vascular endothelial growth factor and its receptors in an aphthous ulcer J Cutan Med Surg 2003;7225- 228PubMedGoogle ScholarCrossref 4. Margolis DJBilker WSantanna JBaumgarten M Venous leg ulcer: incidence and prevalence in the elderly J Am Acad Dermatol 2002;46381- 386PubMedGoogle ScholarCrossref 5. Phillips TJMachado FTrout RPorter JOlin JFalanga V Prognostic indicators in venous ulcers J Am Acad Dermatol 2000;43627- 630PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

Combination Therapy of Doxycycline and Topical Tacrolimus for Venous Ulcers

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References (5)

Publisher
American Medical Association
Copyright
Copyright © 2005 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archderm.141.11.1476
Publisher site
See Article on Publisher Site

Abstract

Venous ulcers are common and debilitating skin lesions that occur predominantly in the lower extremities of elderly patients. They are associated with trauma and varicose veins and are highly susceptible to contact allergies to topical antibiotics, including bacitracin. Pain and infections are major causes of morbidity in patients with venous ulcers. Multiple therapies have been attempted for venous ulceration with varying degrees of success. Recently, it has been recognized that certain subsets of ulcers are highly angiogenic and that high levels of angiogenesis may prevent optimal reepithelialization.1-3 We found that patients with recessive dystrophic epidermolysis bullosa, a deficiency of collagen type VII in which ulceration is a prominent feature, have abnormally high levels of the proangiogenic factor basic fibroblast growth factor (bFGF).2 Doxycycline, a commonly used antibiotic for acne, is an effective inhibitor of matrix metalloproteinases. Given these findings, we successfully used combination therapy of doxycycline and tacrolimus for the treatment of long-standing venous ulceration in a patient who did not tolerate compression stockings. Given our success, larger studies of this therapy are justified. Report of a Case A 71-year-old woman presented with a 6-month history of moderately painful nonhealing ulcerations on her left lower extremity. On clinical examination she was found to have several superficial ulcers ranging in size from 1 to 3 cm distributed on and near her left lateral and medial ankle. The base of the ulcers contained granulation tissue and some yellow fibrinous debris. The borders were not undermined. She had significant background erythema of her left leg and pitting edema to her knee. She also had multiple medical problems, including myelodysplastic syndrome, and she was undergoing treatment with several systemic medications, including warfarin sodium and cyclosporine. She did not respond to initial treatment, which included broad-spectrum antibiotics, limb elevation, and local wound care, and did not tolerate compression stockings. A biopsy specimen revealed dermal and cutaneous sclerosis consistent with stasis changes. There was no evidence of vasculitis or vasculopathy. At that time, she was treated with 0.1% topical tacrolimus ointment twice daily with 100 mg of doxycycline hyclate by mouth twice daily. After 2 weeks, the ulcers were markedly improved, smaller, and less painful, and at 2 months, the ulcerations were nearly completely reepithelialized (Figure 1). We have treated 2 other patients with long-standing (>1 year) venous ulceration and have noted similar results. Figure 1. View LargeDownload Before and after photographs of a patient with venous ulcers. A, Venous ulceration on the patient’s leg prior to treatment. B, Patient’s leg after 2 months of combination therapy with doxycycline hyclate and 0.1% topical tacrolimus. Comment Venous ulcers are a common cause of morbidity, especially in the elderly. Multiple factors are associated with venous ulcers, including dependency, varicose veins, contact allergy to topical products, bacterial colonization, and impaired barrier function (Figure 2).4,5 Multiple therapies have been used for the treatment of venous ulceration, including grafting, topical growth factors, and hyperbaric oxygen. These therapies are very expensive and not universally effective. Figure 2. View LargeDownload A model of venous ulceration. Impaired barrier function is associated with increased synthesis and release of angiogenic growth factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The bed of the ulcer is colonized with bacteria, leading to activation of proinflammatory toll receptors (TLR2 and TLR4). Neutrophils and other mononuclear cells release proangiogenic interleukin 8 (IL-8) and matrix metalloproteinases (MMPs). The proinflammatory and highly angiogenic environment causes inhibition of reepithelialization, resulting in persistence of venous ulceration. Recently, it has been recognized that a subset of ulcers, including venous ulcers, are highly angiogenic. Increased angiogenesis is associated with the failure of epithelialization, which is often noted in cutaneous hemangiomas and neoplasms. Thus, the increased angiogenesis associated with venous ulcers may be the cause of the failure to epithelialize. We report a case that responded to the combination of topical tacrolimus and oral doxycycline. Larger studies are warranted to determine whether this simple mode of treatment should be used as first-line therapy for venous ulcers. Back to top Article Information Correspondence: Dr Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Dr, Atlanta, GA 30322 (jarbise@emory.edu). Financial Disclosure: None. Funding/Support: This work was supported by Emory Skin Disease Research Core Center grants RO1 AR47901and P30 AR42687 (Dr Arbiser) from the National Institutes of Health, Bethesda, Md. References 1. Arbiser JL Angiogenesis and the skin: a primer J Am Acad Dermatol 1996;34486- 497PubMedGoogle ScholarCrossref 2. Arbiser JLFine JDMurrell D et al. Basic fibroblast growth factor: a missing link between collagen VII, increased collagenase, and squamous cell carcinoma in recessive dystrophic epidermolysis bullosa Mol Med 1998;4191- 195PubMedGoogle Scholar 3. Arbiser JLJohnson DCohen CBrown LF High-level expression of vascular endothelial growth factor and its receptors in an aphthous ulcer J Cutan Med Surg 2003;7225- 228PubMedGoogle ScholarCrossref 4. Margolis DJBilker WSantanna JBaumgarten M Venous leg ulcer: incidence and prevalence in the elderly J Am Acad Dermatol 2002;46381- 386PubMedGoogle ScholarCrossref 5. Phillips TJMachado FTrout RPorter JOlin JFalanga V Prognostic indicators in venous ulcers J Am Acad Dermatol 2000;43627- 630PubMedGoogle ScholarCrossref

Journal

Archives of DermatologyAmerican Medical Association

Published: Nov 1, 2005

Keywords: doxycycline,combined modality therapy,varicose ulcer,tacrolimus

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