Clinical Efficacy of Human Split-Thickness Skin Allograft in Patients With Pyoderma Gangrenosum

A Case Series

Angela N. Anaeme, BS; Ariel R. Darnall, DO; Kenneth Anaeme, MD

Disclosures

Wounds. 2022;34(6):165-174. 

In This Article

Abstract and Introduction

Abstract

Introduction: Pyoderma gangrenosum (PG) is an uncommon inflammatory skin disease that is characterized clinically by the development of painful pustules that subsequently progress to large cutaneous ulcers. There is no universally effective treatment for PG, and a combination of local and systemic therapies is often used to manage it. Biologically active, cryopreserved human skin allograft (BSA) has become a standard part of the treatment algorithm for complex nonhealing wounds. These allografts facilitate the wound healing cascade by delivering the essential biologically active compounds of fresh skin to the wound bed and promoting wound bed revascularization.

Objective: The purpose of this case series was to illustrate how the use of human split-thickness allografts positively contributes to wound healing in patients with PG.

Case Presentations: Five cases highlighting the efficacy of a BSA in achieving clinical wound healing in patients with complex PG ulcerations are presented. Clinical findings appear to indicate that the positive effect of BSA in combination with systemic therapies on wound beds in patients with PG is because of a combination of both the unique alterations in the patient's immune system in addition to the possible delays in clearance of cellular components of the allograft, which promote the strong inosculation and revascularization necessary for wound healing.

Conclusions: The BSA studied herein appears to aid in wound healing because it has natural components found in human skin that facilitate wound healing, and it eliminates the potential for pathergy because no graft harvesting from the host is performed. These allografts can be applied numerous times, and each has the major essential components of human skin wound healing for a more rapid and complete epithelialization.

Introduction

Pyoderma gangrenosum (PG) is a rare, painful ulcerative dermatosis that is difficult to diagnose and manage because of its variable, nonspecific histopathologic and laboratory findings. Although up to 50% of PG cases are associated with systemic disease, many cases are idiopathic and are not associated with systemic disease.[1,2] No clear pathogenesis has been identified in the development of PG. Initially, it was thought that PG was caused primarily by neutrophilic abnormalities; however, more recent research suggests the dysfunction related to neutrophilic chemotaxis is thought to involve abnormalities in the inflammatory cascade that lead to defective neutrophil presentation.[3] Leading theories suggest the pathogenesis is multifactorial and involves a combination of inflammatory cytokine dysfunction, with neutrophilic and T-cell abnormalities contributing to immune system malfunction.[2,3] The elevation in proinflammatory cytokines such as interleukin (IL)-1, IL-1β, IL-8, and IL-17 as well as matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial growth factor, and tumor necrosis factor alpha have been shown to affect the development of PG.[3,4]

Traditionally, PG manifests as a painful ulceration, most commonly in the lower extremities and especially in the pretibial area. Adults are the primary age group affected by PG, with most patients between 20 and 50 years of age.[1,5–7] The 4 clinical variants of PG are ulcerative, pustular, bullous, and superficial/granulomatous/vegetative.[2] These 4 variants manifest differently clinically in both presentation and progression, as well as in terms of histologic manifestations and associated systemic diseases.

Typically, PG begins as a small papule, pustule, nodule, or vesicle with an erythematous or violaceous base. Within a few days, the lesion quickly transforms into a rapidly enlarging area of central necrosis. Fully developed lesions present as a painful ulceration with a purulent, necrotic base with an undermined, irregular edematous and erythematous border; these are the classic features associated with PG. Typically, the bordering periwound tissue is surrounded by a combination of acneiform and serpiginous morphology with a violaceous/lilac or erythematous ring of color. These ulcerations can be deep or shallow, with deeper lesions sometimes resulting in exposed tendon, muscle, and bone in severe cases. Acute lesions tend to progress quickly, with associated pain that is severe but responsive to the administration of systemic steroids. Chronic lesions that heal with cribriform scar support a diagnosis of PG.[8]

Pyoderma gangrenosum has a distinctive clinical morphology; however, it is important to rule out other more likely diagnoses, including follicular and soft tissue infections, parasitic infections, vasculitic conditions, vascular diseases, lymphomas, drug reactions, other neutrophilic dermatoses, malignancies, myriad inflammatory conditions, and even insect bites.[1,9] The histopathologic findings of PG are relatively nonspecific. However, early lesions tend to exhibit a dense neutrophilic or lymphocytic perivascular infiltrate, whereas older lesions exhibit a more mixed inflammatory infiltrate with evidence of epidermal necrosis and ulceration or infarction.[10,11] These features may aid in the diagnosis of PG, and they are the only major criteria used in diagnosing ulcerative PG.[8] There are 9 diagnostic criteria of ulcerative PG, with 1 major criterion (biopsy revealing neutrophilic infiltrate) and 8 minor criteria (exclusion of infection on histology; evidence of pathergy; a history of inflammatory bowel disease or inflammatory arthritis; a papule/pustule/vesicle that rapidly ulcerates; periwound peripheral erythema, undermining border, and tenderness; multiple lesions with at least 1 on the anterior lower leg; a cribriform scar at healed lesion sites; and a decrease in ulcer size with immunosuppressive treatment).[8] The major criterion, in addition to 4 of the 8 criteria, must be met to diagnose ulcerative PG. No specific immunologic dysfunction has been universally identified among all patients with PG, although in 1986 Su et al reported a possible immunopathologic correlation to PG.[10] Findings revealed direct immunofluorescence positivity in the blood vessels of 55% of specimens from patients with PG, in addition to immunoglobulin M, complement 3, and fibrin in dermal vessels, although these latter 3 findings are not specific to PG.[10]

Pyoderma gangrenosum is relatively rare, and the incidence has not been well established because of a lack of controlled clinical trials. The estimated incidence of PG varies from approximately 3 to 10 cases per million per year in Italy[2,12] to an incidence possibly closer to 1 in every 100 000 persons per year in the United Kingdom.[13,14] As a result of a combination of all the aforementioned factors, management options for PG have been limited and not particularly effective.

There is no universally effective treatment for PG. Typically, treatment options are either local or systemic.[15] Local treatments aim to provide pain relief, manage secondary bacterial infections, and provide a stable environment for wound healing. Wet compresses, sterile saline, antiseptic solutions, and absorbent dressings are a few examples of local treatment methods used to improve wound healing. The management of PG can be optimized depending on whether the lesion or lesions are in the inflammatory or the noninflammatory phase.[16] During the inflammatory phase, the objective of local management is to reduce the inflammation to the area using medium- to high-potency topical corticosteroids, tacrolimus, or pimecrolimus, in the wound bed and the periwound skin. In this phase, surgical or mechanical debridement of the wound bed is avoided, and the ulcer is typically managed with a combination of autolytic or enzymatic debridement, antiseptics, and steroids followed by coverage with an occlusive dressing.[16] During the noninflammatory phase, periwound treatment is unnecessary unless secondary skin dermatoses are present. In the noninflammatory healing phase, the wound bed is amenable to surgical debridement and the use of skin substitutes.[16] Localized therapy can be used alone in the setting of mild disease.

In contrast, systemic treatments target the underlying clinical pathology, thus promoting healing at the PG wound sites. Forms of systemic therapy include intravenous high-dose pulse steroid therapy, diaminodiphenylsulfone (dapsone), clofazimine, and immunosuppressive therapy.[15] Immunosuppressive therapy is more commonly used in multilesional or widespread disease. These medications include first-line agents such as cyclosporine A or infliximab, or second-line immunosuppressive agents such as cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, and methotrexate.[17–19] A combination of local and systemic treatment often yields the best results.

This case series presents information on the efficacy of TheraSkin (Bioventus), a human bioactive skin allograft (BSA), in the management of PG ulcers. Limited information exists about the use of allografts in patients with PG, and a thorough demonstration of the BSA studied herein on PG ulcers is incomplete. Although skin allografts have been acknowledged as a viable treatment option for patients with PG, notable controversy persists concerning their merit because of the potential for inducing periwound skin complications. In a case report, Araújo et al[20] stated that the use of skin allografts in the management of PG wounds "remains … a topic of discussion" despite being "well documented in the literature as an option in selected cases."

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