Leg Ulcers: Expanding the Differential
- 28 Downloads
Purpose of Review
Cutaneous lower extremity ulcerations are major source of morbidity and mortality. It can be challenging to identify an underlying etiology. This review provides a systematic framework for generating a thoughtful differential diagnosis and workup approach. We also highlight recent discoveries in the pathophysiology and treatment approaches of leg ulceration.
Venous leg ulceration is being treated with a number of promising new modalities including pentoxifylline, statin therapy, topical timolol, connexin-43 peptide antagonists, photodynamic therapy, and punch grafting. The role of vitamin K deficiency is gaining prominence with regard to calciphylaxis.
Recognition of key risk factors and subtle physical exam findings can serve as clues to the underlying mechanism of cutaneous ulceration and direct a targeted workup for underlying systemic disease that may be ameliorated with appropriate therapy.
KeywordsLeg ulcer Venous ulcer Calciphylaxis Pyoderma gangrenosum Livedoid vasculopathy
Compliance with Ethical Standards
Conflict of Interest
Dr. Keller has no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
- 2.•• Morton LM, Phillips TJ. Wound healing and treating wounds: differential diagnosis and evaluation of chronic wounds. J Am Acad Dermatol. 2016;74(4):589–605. Reviews stages of wound healing and pathophysiology of chronic wounds. Reviews differential diagnosis and evaluation for chronic wounds of unknown etiology. CrossRefPubMedCentralGoogle Scholar
- 8.• Forssgren A, Nelzén O. A repeat validated population questionnaire of a defined Swedish population verifies reduction in leg ulcer prevalence over time. Acta Derm Venereol. 2015;95(6):725–9. In Skaraborg County, Sweden, a large follow-up population-based survey estimates a 50% reduction in venous leg ulcer prevalence in a community of 250,000 following initiation of a widespread multidisciplinary treatment strategy implemented over a decade. CrossRefPubMedCentralGoogle Scholar
- 9.• Reeder S, de Roos KP, de Maeseneer M, Sommer A, Neumann HA. Ulcer recurrence after in-hospital treatment for recalcitrant venous leg ulceration. Br J Dermatol. 2013;168(5):999–1002. Multicenter retrospective cohort study of inpatients treated for venous leg ulceration demonstrates reduction in length of hospital stay with surgical treatment. However, most ulcers recurred within 2 months following hospital discharge, highlighting the need for intensive outpatient follow up. CrossRefPubMedCentralGoogle Scholar
- 10.• Zarchi K, Jemec GB. Delivery of compression therapy for venous leg ulcers. JAMA Dermatol. 2014;150(7):730–6. Cross-sectional outpatient study demonstrates wide variation in pressures achieved with compression therapy and that only half achieved optimal subbandange pressure of 30-50mmHg. This study highlights the opportunity for standardized training programs for delivery of compression therapy. CrossRefPubMedCentralGoogle Scholar
- 20.• Ghatnekar GS, Grek CL, Armstrong DG, Desai SC, Gourdie RG. The effect of a connexin43-based peptide on the healing of chronic venous leg ulcers: a multicenter, randomized trial. J Invest Dermatol. 2015;135(1):289–98. The gap junction protein connexin-43 is known to be upregulated in wound margins of venous leg ulcers. This proof-of-concept prospective multicenter randomized controlled trial of 92 patients demonstrates that mean percent ulcer reepithelialization is significantly increased at 12 weeks using a topical gel containing ACT1, a mimetic peptide of connexin-43. CrossRefPubMedCentralGoogle Scholar
- 21.• Martínez ML, Escario E, Poblet E, Sanchez D, Buchon FF, Izeta A, et al. Hair follicle-containing punch grafts accelerate chronic ulcer healing: a randomized controlled trial. J Am Acad Dermatol. 2016;75(5):1007–14. This randomized controlled trial of 12 patients demonstrates significantly increased percent reduction of ulcer area when using punch grafts containing terminal hair follicles compared to non-hair bearing punch grafts. CrossRefPubMedCentralGoogle Scholar
- 25.•• Yu WY, Bhutani T, Kornik R, Pincus LB, Mauro T, Rosenblum MD, et al. Warfarin-associated nonuremic calciphylaxis. JAMA Dermatol. 2017;153(3):309–14. This case series and review of the literature posits that warfarin-associated nonuremic calciphylaxis is a distinct entity. It differs from uremic calciphylaxis in that it tends to be limited to distal lower extremities and appears to have a higher survival rate. Notably treatment is aimed at replacing warfarin with heparin-based products. CrossRefPubMedCentralGoogle Scholar
- 36.Castillo-Martínez C, Moncada B, Valdes-Rodriguez R, Gonzalez FJ. Livedoid vasculopathy (LV) associated with sticky platelets syndrome type 3 (SPS type 3) and enhanced activity of plasminogen activator inhibitor (PAI-1) anomalies. Int J Dermatol. 2014;53(12):1495–7.CrossRefPubMedCentralGoogle Scholar
- 40.• Riyaz N, Sasidharanpillai S, Rahima S, Bindu V, Shaan M, Raghavan NT, et al. Pyoderma gangrenosum in association with microscopic colitis, idiopathic hypereosinophilic syndrome, selective IgE deficiency and diabetes mellitus. Clin Exp Dermatol. 2015;40(6):629–32. In this case report, three rare conditions not previously associated with pyoderma gangrensoum are reported coexistent in the same patient, possibly hinting at an underlying genetic basis. Furthermore it is postulated that microscopic colitis is a risk factor for pyoderma gangrenosum. CrossRefPubMedCentralGoogle Scholar
- 54.• Morley S, Griffiths J, Philips G, Moseley H, O’Grady C, Mellish K, et al. Phase IIa randomized, placebo-controlled study of antimicrobial photodynamic therapy in bacterially colonized, chronic leg ulcers and diabetic foot ulcers: a new approach to antimicrobial therapy. Br J Dermatol. 2013;168(3):617–24. This study of PDT for chronic ulcers with bacterial colonization showed a significant reduction in bacterial load compared to placebo, as well as a trend toward improved long-term wound healing during follow up. CrossRefPubMedCentralGoogle Scholar
- 58.Valois A, Waton J, Avenel-Audran M, Truchetet F, Collet E, Raison-Peyron N, et al. Dermatology and allergy group (GAD) of the French Society of Dermatology. Contact sensitization to modern dressings: a multicentre study on 354 patients with chronic leg ulcers. Contact Dermatitis. 2015;72(2):90–6.CrossRefPubMedCentralGoogle Scholar