The definition of the venous ulcer

Abstract

An estimated 25 million people in the United States have varicose veins, 2 to 6 million have more advanced chronic venous insufficiency (swelling, skin changes), and either active or healed chronic venous ulcers (CVU) are seen in about 1% of the adult population, of which 500,000 are active venous ulcers (grade: high, population-based studies).1Beebe-Dimmer J.L. Pfeifer J.R. Engle J.S. Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins.Ann Epidemiol. 2005; 15: 175-184Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 2White J.V. Ryjewski C. Chronic venous insufficiency.Perspect Vasc Surg Endovasc Ther. 2005; 17: 319-327Crossref PubMed Scopus (51) Google Scholar, 3Etufugh C.N. Phillips T.J. Venous ulcers.Clin Dermatol. 2007; 25: 121-130Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Venous ulcers usually occur at the malleolar region both on the medial and lateral aspects of the ankle. However, they are also known to occur on the supra-malleolar and infra-malleolar regions of the leg and foot, respectively. According to the revised CEAP classification published in 2004, a venous ulcer is defined as: full-thickness defect of the skin, most frequently in the ankle region, that fails to heal spontaneously and is sustained by chronic venous disease (grade: low-very low, clinical observational studies and expert opinion).4Eklöf B. Rutherford R.B. Bergan J.J. Carpentier P.H. Gloviczki P. Kistner R.L. et al.Revision of the CEAP classification for chronic venous disorders: consensus statement.J Vasc Surg. 2004; 40: 1248-1252Abstract Full Text Full Text PDF PubMed Scopus (1395) Google Scholar Although this definition provides a description of a venous ulcer, it leaves much to be interpreted. For example, venous ulcers that occur in the ankle region may have different biologic activity and healing properties than those in other regions of the leg. The depth of the ulcer may be different for certain full thickness ulcers (1-2 mm depth) vs those that are 5 to 10 mm in depth. A wound bed score (0-16, higher score better wound bed score) that encompasses several parameters including healing edges (wound edge effect), presence of eschar, greatest wound depth/granulation tissue, amount of exudates, amount of edema, peri-wound dermatitis, peri-wound callus and or fibrosis, and a pink/red wound bed, has demonstrated to be useful in determining wounds that heal vs wounds that are resistant to heal (grade: low, clinical observational study).5Falanga V. Saap L.J. Ozonoff A. Wound bed score and its correlation with healing of chronic wounds.Dermatol Ther. 2006; 19: 383-390Crossref PubMed Scopus (71) Google Scholar, 6Kerstein M.D. Brem H. Giovino K.B. Sabolinski M. Development of a severity scale for evaluating the need for Graftskin in nonhealing venous ulcers.Adv Skin Wound Care. 2002; 15: 66-71Crossref PubMed Scopus (7) Google Scholar These findings would indicate that CVUs have different biologic activity, and should not all be categorized alike as a single common venous ulcer. Quantitative instruments to measure ulcer depth, area, and contour are available, but not commonly used in clinical practice, and such measurements are usually reserved for research trials (grade: low, clinical observational study).7Altmeyer P. Erbler H. Krömer T. Duwe H.P. Hoffmann K. Interferometry: a new method for no-touch measurement of the surface and volume of ulcerous skin lesions.Acta Derm Venereol. 1995; 75: 193-197PubMed Google Scholar, 8Kecelj-Leskovec N. Jezersek M. Mozina J. Pavlović M.D. Lunder T. Measurement of venous leg ulcers with a laser-based three-dimensional method: comparison to computer planimetry with photography.Wound Repair Regen. 2007; 15: 767-771Crossref PubMed Scopus (27) Google Scholar The importance of using quantitative instruments is to standardize the evaluation of ulcers, recognize differences in ulcers, and remove bias in studies that are evaluating different therapies in treating CVUs. The duration and size of a CVU are important factors in determining the potential to heal vs those ulcers that do not, also suggesting different biological activity of CVUs (grade: low, clinical observational studies).5Falanga V. Saap L.J. Ozonoff A. Wound bed score and its correlation with healing of chronic wounds.Dermatol Ther. 2006; 19: 383-390Crossref PubMed Scopus (71) Google Scholar, 6Kerstein M.D. Brem H. Giovino K.B. Sabolinski M. Development of a severity scale for evaluating the need for Graftskin in nonhealing venous ulcers.Adv Skin Wound Care. 2002; 15: 66-71Crossref PubMed Scopus (7) Google Scholar, 9Phillips T.J. Machado F. Trout R. Porter J. Olin J. Falanga V. Prognostic indicators in venous ulcers.J Am Acad Dermatol. 2000; 43: 627-630Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 10Meaume S. Couilliet D. Vin F. Prognostic factors for venous ulcer healing in a non-selected population of ambulatory patients.J Wound Care. 2005; 14: 31-34PubMed Google Scholar Venous ulcer duration, crude size, and number of ulcers are important parameters that have been incorporated in the venous clinical severity score in an effort to quantify disease severity (grade: low-very low, clinical observational studies and expert opinion).11Rutherford R.B. Padberg Jr, F.T. Comerota A.J. Kistner R.L. Meissner M.H. Moneta G.L. Venous severity scoring: an adjunct to venous outcome assessment.J Vasc Surg. 2000; 31: 1307-1312Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar It is important also to note that the prevalence of lower extremity ulceration presenting at vascular clinics that is not of venous or arterial etiology, and which usually involves the medial lower calf, is 2.1%. These ulcers have etiologies that include: neoplasia, chronic inflammation, sickle cell disease, vasculitis, rheumatoid arthritis, pyoderma gangrenosum, hydroxyurea, and nonspecific cause, indicating the importance of performing a biopsy and/or hematologic/serologic evaluation in non-healing atypical presentations of leg ulcers (grade: low, clinical observational study).12Labropoulos N. Manalo D. Patel N.P. Tiongson J. Pryor L. Giannoukas A.D. Uncommon leg ulcers in the lower extremity.J Vasc Surg. 2007; 45: 568-573Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Published studies that evaluate adjuvant therapies in venous ulcers, whether topical or systemic agents, or surgical procedures in conjunction with compression lack clarity in defining a chronic venous ulcer (grade: high-low, clinical randomized controlled trials and observational studies).13Gohel M.S. Barwell J.R. Taylor M. Chant T. Foy C. Earnshaw J.J. et al.Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial.BMJ. 2007; 335: 83Crossref PubMed Scopus (293) Google Scholar, 14Falanga V. Margolis D. Alvarez O. Auletta M. Maggiacomo F. Altman M. et al.Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent Human Skin Equivalent Investigators Group.Arch Dermatol. 1998; 134: 293-300Crossref PubMed Scopus (544) Google Scholar, 15Falanga V. Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers.Wound Repair Regen. 1999; 7: 201-207Crossref PubMed Scopus (293) Google Scholar, 16Mostow E.N. Haraway G.D. Dalsing M. Hodde J.P. King D. OASIS Venus Ulcer Study GroupEffectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial.J Vasc Surg. 2005; 41: 837-843Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 17Milio G. Minà C. Cospite V. Almasio P.L. Novo S. Efficacy of the treatment with prostaglandin E-1 in venous ulcers of the lower limbs.J Vasc Surg. 2005; 42: 304-308Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 18Coleridge-Smith P. Lok C. Ramelet A.A. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction.Eur J Vasc Endovasc Surg. 2005; 30: 198-208Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 19Beckert S. Warnecke J. Zelenkova H. Kovnerystyy O. Stege H. Cholcha W. et al.Efficacy of topical pale sulfonated shale oil in the treatment of venous leg ulcers: a randomized, controlled, multicenter study.J Vasc Surg. 2006; 43: 94-100Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 20Senet P. Bon F.X. Benbunan M. Bussel A. Traineau R. Calvo F. et al.Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers.J Vasc Surg. 2003; 38: 1342-1348Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 21Belcaro G. Cesarone M.R. Nicolaides A.N. De Sanctis M.T. Incandela L. Geroulakos G. Treatment of venous ulcers with pentoxifylline: a 6-month randomized, double-blind, placebo controlled trial.Angiology. 2002; 53: S45-S47PubMed Google Scholar Several study examples will illustrate the significant variability of patients with CVU, inclusion criteria, and how CVU are defined. (1) In a large randomized trial evaluating compression plus surgery vs compression alone for CVU (ESCHAR study), the inclusion criteria were patients with venous ulcer (active or recently healed within 6 months) assessed by clinical examination and color venous duplex ultrasound scan, with ulcers located between the knee and malleoli, duration of 3 to 11 months, diameter of 1 to 5 cm, and an ankle-brachial index (ABI) of 0.85 or higher (grade: high, clinical randomized trial).13Gohel M.S. Barwell J.R. Taylor M. Chant T. Foy C. Earnshaw J.J. et al.Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial.BMJ. 2007; 335: 83Crossref PubMed Scopus (293) Google Scholar (2) In a large multicenter trial evaluating human skin equivalent (Apligraf, Organogenesis Inc, Canton, Mass), patients with CVU defined by clinical examination and plethysmography, and an ABI of equal to or greater than 0.65 were randomized to compression plus human skin equivalent or compression alone (grade: high, clinical randomized trial). The venous ulcer area was highly variable with ulcer durations of several months to greater than 2 years.14Falanga V. Margolis D. Alvarez O. Auletta M. Maggiacomo F. Altman M. et al.Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent Human Skin Equivalent Investigators Group.Arch Dermatol. 1998; 134: 293-300Crossref PubMed Scopus (544) Google Scholar A follow-up study of the subgroup of patients with ulcers of greater than 1 year duration was also evaluated.15Falanga V. Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers.Wound Repair Regen. 1999; 7: 201-207Crossref PubMed Scopus (293) Google Scholar (3) In a small, randomized, single center trial, patients with CVUs of venous etiology defined by clinical examination and history, positive venous reflux, had ulcer duration ranging from 1 month to greater than 12 months, with surface areas ranging from 1.05 to 58.8 cm2, and ABI of 0.85 or higher were randomized to compression plus extracellular matrix small intestinal submucosa wound matrix vs compression alone (grade: low, single center clinical observational study).16Mostow E.N. Haraway G.D. Dalsing M. Hodde J.P. King D. OASIS Venus Ulcer Study GroupEffectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial.J Vasc Surg. 2005; 41: 837-843Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar (4) In a randomized, placebo controlled, single blinded study that evaluated intravenous prostaglandin E1 and venous ulcer healing (grade: low, single center clinical observational study).17Milio G. Minà C. Cospite V. Almasio P.L. Novo S. Efficacy of the treatment with prostaglandin E-1 in venous ulcers of the lower limbs.J Vasc Surg. 2005; 42: 304-308Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar This study enrolled patients with a CVU by clinical examination, having an ABI of greater than 0.90, with duplex ultrasound scan evidence of venous reflux and/or obstruction, with ulcer durations ranging between 2 to 11 months, and ulcer areas ranging between 3 to 25 cm2. (5) In a meta-analysis of five randomized controlled trials that investigated micronized purified flavonoid fraction as an adjunct to compression in treating CVU (grade: high, meta-analysis of five randomized clinical trials).18Coleridge-Smith P. Lok C. Ramelet A.A. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction.Eur J Vasc Endovasc Surg. 2005; 30: 198-208Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar The patients had clinical demonstration of venous disease and ulcers, with duplex ultrasound scan to confirm valvular insufficiency, an ABI of greater than 0.80, ulcer durations that ranged between 3 months and greater than 12 months, and ulcer areas of less than 5 cm2, 5 to 10 cm2, and greater than 10 cm2. (6) In a randomized, observer blinded, multicenter study, pale sulfonated shale oil was evaluated as an adjunct to compression therapy in treating CVU (grade: low, single center clinical observational study).19Beckert S. Warnecke J. Zelenkova H. Kovnerystyy O. Stege H. Cholcha W. et al.Efficacy of topical pale sulfonated shale oil in the treatment of venous leg ulcers: a randomized, controlled, multicenter study.J Vasc Surg. 2006; 43: 94-100Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Patients had clinical evaluations for venous disease and duplex ultrasound scan to confirm valvular reflux. The ABI was greater than 0.80, wound areas ranged from less than 20 cm2 to greater than 35 cm2, and duration of ulcer from about 3 months to more than 70 months. These studies, although conducted in randomized and observational methods, illustrate the significant variability of CVU characteristics and patient inclusion criteria with wide variability in duration and size of venous ulcers. The wide variability in how venous ulcers are defined/represented supports the need for research in providing clear and defined baseline ulcer parameters, and devising a venous ulcer scaling system that will include ulcer location, etiology, pathophysiology, ulcer bed characteristics, size, and duration, in an effort to have standardization in definition and inclusion into studies that are assessing therapeutic effectiveness and outcomes. Venous ulcers are known to have significant molecular changes that involve cellular alterations in growth factors specifically transforming growth factors, mitogen-activated protein kinase pathways, and production of matrix metalloproteinases (grade: low, basic science observational studies).22Pappas P.J. DeFouw D.O. Venezio L.M. Gorti R. Padberg Jr, F.T. Silva Jr, M.B. et al.Morphometric assessment of the dermal microcirculation in patients with chronic venous insufficiency.J Vasc Surg. 1997; 26: 784-795Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 23Raffetto J.D. Gram C.H. Overman K.C. Menzoian J.O. Mitogen-activated protein kinase p38 pathway in venous ulcer fibroblasts.Vasc Endovascular Surg. 2008; 42: 367-374Crossref PubMed Scopus (15) Google Scholar, 24Weckroth M. Vaheri A. Lauharanta J. Sorsa T. Konttinen Y.T. Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers.J Invest Dermatol. 1996; 106: 1119-1124Crossref PubMed Scopus (205) Google Scholar It has recently been demonstrated that cytokine production and cytokine metabolism are intimately associated with CVU healing (grade: low, basic science observational study).25Herouy Y. May A.E. Pornschlegel G. Stetter C. Grenz H. Preissner K.T. et al.Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation.J Invest Dermatol. 1998; 111: 822-827Crossref PubMed Scopus (113) Google Scholar, 26Beidler S.K. Douillet C.D. Berndt D.F. Keagy B.A. Rich P.B. Marston W.A. Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy.J Vasc Surg. 2009; 49: 1013-1020Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar CVUs were evaluated for 4 weeks after compression in 30 limbs, and tissue dermal biopsies were obtained before and after compression and analyzed by multiplex protein assay. Pro-inflammatory cytokine were elevated in ulcer tissue compared to healthy tissue. Compression therapy significantly reduced pro-inflammatory cytokines (interleukin [IL]-1α, IL-1β, interferon [IFN]-γ, IL-12p40, and granulocyte-macrophage colony-stimulating factor [GM-CSF]). Transforming growth factor-β1 was upregulated in ulcer tissue after compression therapy. Rapid healing CVUs had significantly increased levels of IL-1α, IL-1β, IFN-γ, IL-12p40, and GM-CSF before compression therapy, and IL-1 Ra after therapy. IFN-γ levels significantly decreased after therapy in the rapidly healing patients. These data suggest that CVU healing is associated with a pro-inflammatory environment indicating metabolically active wound tissue that has the potential to heal. Compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra. Although the study is small and of short duration, it is an important study that has begun to define the molecular environment of active CVUs, and uses biologic markers as parameters that define ulcers on a different level from the customary CVU duration, size, and location. Future investigations in biologic markers hold promise that may potentially define important biologic differences in CVUs and promote standardization in how CVUs are defined. Based on current studies that have investigated the evaluation, diagnosis, baseline ulcer characteristics, measurements of CVUs, and biochemical markers, it is important to note that venous ulcers have differential behavior, and that the assessment of CVUs is complex with multifactorial parameters that may strongly influence healing potential. Therefore, it is of paramount importance that CVUs be properly defined to enable precise characterization and standardization, which will influence study design and inclusion in assessing natural history and epidemiology, genetics, prognostic indicators and predictors of healing, and clinical trials assessing different treatment modalities that will ultimately improve healing and reduce recurrence of CVUs.