Advanced Treatment Options of Pyoderma Gangrenosum Ulcers

Introduction. Pyoderma gangrenosum (PG) is a neutrophilic dermatosis often associated with autoimmune disease that, despite published literature, still poses diagnostic and therapeutic challenges due to its lack of serological and histological markers and wide possibility of differential diagnosis. Although immunosuppressive therapy usually is the first-line treatment, it has a long-lasting, unpredictable treatment course, thus necessitating the need for new treatment options. This report highlights 2 cases of PG ulcers treated with different methods that show a potentially faster healing time, as well as a review of advanced treatment options for PG. Case Reports. Two men (21 years old and 64 years old) presented with PG ulcers and underwent 2 different treatment courses. The 21-year-old man received negative pressure wound therapy (NPWT) with a nonadhesive, less-invasive, skin-contact interface layer on the polyurethane foam. Stimulated growth of granulation tissue accelerated healing and prepared the wound bed for further epithelization. The second patient, the 64-year-old man, underwent treatment with autologous platelet-rich fibrin, which supplied the ulcer with growth factors and accelerated epithelialization. Conclusions. The new possibilities offered by NPWT with nonadhesive foam and regenerative medicine are typically affordable, effective, safe, and painless for the patient. Both methods were noninvasive, did not accelerated the pathergy phenomenon, and showed a potential for faster healing of PG ulcers. 

Pyoderma gangrenosum (PG) is often associated with autoimmune disease and is a neutrophilic dermatosis, characterized by a wide range of clinical presentations, among which recurrent cutaneous ulcerations are the most characteristic.¹ It equally affects both men and women, and peak incidence is between 20 and 50 years of age.² Most frequently, it appears on the pretibial area, head, and neck.³ Pyoderma gangrenosum also can develop extracutaneous symptoms, which most commonly affect the eyes, spleen, musculoskeletal system, and lungs.^4,5 The extracutaneous symptoms are particularly common in patients with underlying diseases, such as inflammatory bowel disease (IBD), inflammatory arthritis, and hematological diseases, which are present in up to 75% of cases.^4-6 Therefore, all patients should be evaluated for any potential underlying disease(s). There is no current gold standard treatment for PG. This report includes 2 clinical cases of PG treated with 2 different treatments, which showed potential for faster healing of PG ulcers.

Etiology and diagnosis

The pathophysiology of PG is not yet fully understood. Dysregulation of an innate immune system, abnormal chemotaxis, phagocytosis, and neutrophil migration are potential options that are allegedly responsible for its occurrence.⁷ Pyoderma gangrenosum may occur after injury to the skin, thus it may be triggered by multiple surgical procedures; this phenomenon is referred to as pathergy phenomenon.⁸ Due to a lack of specific serologic and histologic markers, the diagnosis of PG is still made by the exclusion of other cases of cutaneous ulcers.¹ In differential diagnosis, Sweet’s syndrome, Behçet’s disease, and neutrophilic urticaria should be excluded.⁹

Clinical picture

Pyoderma gangrenosum typically presents with sterile pustules, which rapidly progress to painful necrotizing ulcers. The appearance of ulcers depends on the type of the PG. Currently recognized clinical versions of PG are classical, bullous, pustular, vegetative, drug-induced, and postsurgical.¹⁰ Classical PG presents with 2 stages. First is an ulcerative stage, which is characterized by a rapid spread of the wound with a red halo, a central necrosis with a purulent or granulomatous base, and elevated purple edges. Second is a healing stage in which there are epithelium projections from the edges toward the center of the ulcer, and it heals with cribriform scars.^7,11 Bullous PG is associated with underlying hematological malignancies and often occurs in atypical places, such as the dorsum of the hands and extensor parts of the upper limbs.² Pustular PG is most commonly coexistent with IBD and predominantly occurs on the trunk and extensor parts of the limbs in the form of sterile pustules.⁷ The peristomal form occurs in patients who have a formed stoma of any type, including urostomies.² Similar to the pustular form, the peristomal form often occurs with IBD.² The vegetative form of PG is the rarest and most benign form and appears with erythematous superficial verrucous lesions.² Postsurgical PG can appear immediately after or up to 6 weeks following surgery. For its occurrence, the pathergy phenomenon is critical. Pathergy phenomenon means the development of new lesions after trauma of the skin, and it suggests an altered inflammatory response to nonspecific stimuli.⁹ Postsurgical PG most often occurs after breast or cardiothoracic surgeries. In cases of breast involvement, the nipple is usually spared.¹² Pyoderma gangrenosum can mimic surgical wound infection, and its misdiagnosis can lead to unnecessary antibiotic use.⁸

Therapeutic approach

As PG is a rare, noninfectious neutrophilic dermatosis, the main goal of treatment is to modulate the immune response, thus reducing the inflammatory process.¹³ First-line therapy features systemic steroids that can be administered orally. However, intravenous (IV) steroids in high doses might be needed in generalized forms. Second-line therapy includes biologics (tumor necrosis factor alpha inhibitors). In addition to systemic immunosuppressant therapy, topical or intralesional drugs can be used.¹⁴ At the same time, treatment should be directed to possible underlying systemic disease. However, to date, there is no universally accepted therapeutic regimen. It is known that after 6 months of immunosuppressive therapy, less than 50% of patients will achieve complete wound healing, with 30% to 60% of relapses.¹⁵ Due to prolonged healing time, PG ulcers are prone to secondary bacterial infections, which additionally prolong the healing time and predispose to pathergy phenomenon.¹⁶ Therefore, additional treatment options are being sought, such as granulocytopheresis, which selectively removes activated granulocytes, macrophages, and circulating inflammatory cytokines from the peripheral blood and surgical techniques.¹⁷

To date, the literature lacks evidence that surgical methods are beneficial for PG treatments. The introduction of surgical treatment as a form of therapy for PG is controversial, as it can lead to pathergy phenomenon and aggravation of this condition. However, satisfactory results of gentle debridement, skin grafting, and reconstruction have been demonstrated.^18,19 Long et al²⁰ showed that puncturing the epidermis and dermis during suturing increases the risk of pathergy phenomenon in a surgical wound. Due to this discovery, it is recommended to only use sutures for the subcutaneous tissue. Suturing of the epidermis is not recommended because excessive skin manipulation can cause pathergy phenomenon.⁹

It is also important to highlight the difference between various suturing materials. According to Long et al,²⁰ silk sutures cause more extensive dermal inflammation than synthetic sutures, such as Dexon (absorbable monofilament suture), thus causing a greater risk of pathergy phenomenon. The first comprehensive review of surgical treatment for PG confirmed split-thickness skin grafting (STSG) and negative pressure wound therapy (NPWT) to be safe treatment options for PG under adequate immunosuppressive therapy.¹⁵ Further, STSG appeared to accelerate wound healing. Pichler et al¹⁵ also proposed a treatment algorithm for PG, in which they recommend a step-by-step approach. First, it is necessary to find and treat an underlying disease and provide a sufficient caloric and protein-saturated diet. Then, adjuvant therapy, such as iloprost, simvastatin, and pentoxifylline, which reduces the possibility of graft failure, should be initiated. Preoperative antibiotic and antithrombotic prophylaxis are required.¹⁵ Preoperatively, NPWT is recommended, as it can provide a good environment to promote healing. At the same time, negative pressure can help to approximate wound edges, remove exudate, and promote perfusion.⁹ Though clinical experiences have been published with no signs of improvement after NPWT.²¹ With STSG, there is also a risk that pathergy phenomenon can accelerate on the donor site. 

The defect of the skin can be closed with a collagen-glycosaminoglycan biodegradable matrix. The artificial bilayer membrane appears to be an effective option to cover the ulcerative lesions gently, thereby avoiding complex surgical treatment such as free tissue transfer. A STSG can be placed on the artificial skin bilayer membrane in a second operation.²² In order to reduce the likelihood of pathergy phenomenon, it is necessary to use immunosuppressive therapy. Also, it is recommended to use systemic corticosteroids; from there, dapsone, infliximab, and other immunosuppressive medications can be added.¹⁵

For the publication of these case reports, written, informed consent was obtained from all patients involved and treated at University Medical Centre Ljubljana in Ljubljana, Slovenia.

Case 1

A 21-year-old man with a history of ulcerative colitis presented with a high fever (38°C) and multiple painful red skin lesions of the lower legs. Due to suspicion of infection, drainage incisions and extensive sharp debridement were performed in the local hospital (Figure 1 and Figure 2). The patient was transferred to the University Medical Centre Ljubljana, because his medical condition was not improving. Based on a history of longstanding ulcerative colitis, appearance of lesions, and lack of improvement after surgical treatment, PG was suspected. A tissue biopsy was performed and sent for histological examination, which was consistent with the diagnosis of PG.

In the intensive care unit, the patient received systemic treatment with 1 mg/kg of IV methylprednisolone and 2 g of IV antibiotic flucloxacillin every 6 hours due to bacterial superinfection with Staphylococcus aureus. A polymeric membrane dressing (PolyMem; Ferris Mfg. Corp, Fort Worth, TX) was applied to the ulcers and changed every 2 to 3 days. After inflammatory parameters declined, postincisional ulcers were approximated with monofilament nylon sutures (Figure 3). On the skin defect, continuous NPWT (-125 mm Hg) with an advanced nonadhesive, less-invasive, skin-contact interface layer of the polyurethane foam was applied for 7 days (PREVENA Incision Management System with CUSTOMIZABLE Dressing Kit; KCI, San Antonio, TX) (Figure 4), to prepare the wound bed with granulation tissue (Figure 5). At 8 weeks, epithelialization of the ulcer edges was in progress, and scar formation had finished (Figure 6).

Case 2

A 64-year-old man presented with an extensive wound (22 cm x 17 cm) on the right side of the neck, with underlying thrombosis of the jugular vein. Initially, he was treated for a subcutaneous abscess with surgical drainage and puss evacuation. In the first 2 days following surgery, his ulcer started to spread rapidly. The pain was severe (visual analogue scale: 7–9). He received analgesics, an anticoagulant (dalteparin), and 1.2 g IV amoxicillin with clavulanic acid every 8 hours. The microbiological results were negative, despite increased inflammatory parameters. A nonadhesive polymeric membrane dressing with silver was applied to the wound (PolyMem Silver; Ferris Mfg. Corp) and changed every 2 days, but the wound did not show any sign of healing (Figure 7).

Due to an atypical course of illness and negative microbiological results, the authors suspected PG could be an alternative diagnosis. A tissue sample was taken for histological examination and was consistent with a diagnosis of PG. After the diagnosis of PG was determined, 1 mg/kg of IV corticosteroid (methylprednisolone) was administered. The large neck ulcer with exposed jugular vein spread further in length and width (24 cm x 19 cm). An autologous platelet-rich fibrin (PRF; Vivostat PRF; Vivostat A/S, Alleroed, Denmark) was applied to the PG ulcer. Supplying the ulcer with growth factors from activated platelets in PRF was essential for tissue regeneration (Figure 8). Immediately following the PRF application the ulcer was covered with polyurethane foam dressings with a silicone contact layer (Mepilex; Mölnlycke Health Care, Gothenburg, Sweden) and were changed every 2 days. The autologous PRF was applied only once. This method showed a powerful treatment option for PG ulcer healing. Despite the successful healing of the ulcer, the patient died 4 weeks later due to bleeding into the retroperitoneal space, which was unrelated to the treatment.

The most effective therapy for treating PG ulcers should be the least invasive option. Any trauma to the ulcer can accelerate pathergy phenomenon. Grafting with STSG and applying NPWT should be used with caution due to the risk of pathergy phenomenon. Therefore, the authors chose a less-invasive NPWT system with an advanced nonadhesive skin-contact interface layer on the polyurethane foam, instead of conventional polyurethane foam (V.A.C. Therapy; KCI), which has been described in the literature.^15,21 The less-invasive NPWT system is primarily intended for application on intact skin after closed surgical incisions with sutures or staples. The skin-contact interface layer under the polyurethane foam in this NPWT system is impregnated with silver, gentle, and nonadherent as well as reduces the risk of pathergy phenomenon, compared with the standard NPWT polyurethane foam. This method is superior to conventional NPWT in terms of preventing pathergy phenomenon; in the authors’ opinion, it could be the gold standard treatment option.

The other successfully used method with application of PRF is also gentle and not harmful to the wound bed. Based on platelet activation, contents of alpha granules are consequently released into the surrounding tissue. Although there are more than 300 different proteins in α-granules,²³ it seems the most important growth factors in platelets are the 3 isomers of platelet-derived growth factors (αα, ββ, and αβ), transforming growth factors (α and β), vascular endothelial growth factor, and epidermal growth factor, because they initiate ulcer healing.^24,25 In the literature^26-28 regarding platelet-rich plasma and PRF in chronic ulcers of different etiologies, there are promising results to promote healing and reduce the circumference and average area of the ulcers.²⁸ In addition, based on the results of the 2 PG cases presented herein, these treatment options can be utilized.

In this article, 2 treatment modalities of PG ulcers were presented with positive outcomes and showed potential for wider use of treatment in patients with diagnosed PG. These 2 patients had different courses of the disease and a different range of ulcers, which resulted in the use of different treatment methods. In the first case, the extent of some ulcers allowed primary suturing of the ulcer, compared with the second case, in which the extent of the ulcer and tissue deficit was too large for primary suturing. In both cases, treatment was based on minimally invasive techniques so as to cause the least amount of trauma to the tissues and protect against faster disease progression. Both methods have proven to be potentially effective methods, but these methods should be tested further. Also, the incidence of PG is not entirely determined and most reports involve single cases or a small series of patients in single hospital.²⁹ Based on the minimal data available, it is essential to perform new prospective multicenter studies in order to validate the statistical effectiveness of the tested methods. 

Pyoderma gangrenosum can be a devastating ulcer-forming disease that can progress rapidly. Even though it is a rare condition, it should always be considered in differential diagnosis for patients with progressive ulceration, especially on surgical sites. Early diagnosis is imperative for a positive outcome. A universally accepted therapeutic regimen to manage and treat PG is still lacking because variability in both the assessment and outcomes of PG make it difficult to compare the effectiveness of different treatment regimens. The new possibilities offered by advanced NPWT and regenerative medicine are typically affordable, effective, safe, and painless for the patient. Future research to better understand the disease and its treatment is highly recommended.

Authors: Danijela Semenič, MD, PhD; Petra Bukovec, MD

Note: The authors thank their colleagues of the maxillofacial surgery, gastroenterologists, and infectious disease specialists at the University Medical Centre Ljubljana (Ljubljana, Slovenia). Special thanks to Primoz Trunk, MD, PhD, for proofreading the article.

Affiliation: Department of Surgical Infections, University Medical Centre Ljubljana and Medical Faculty, University of Ljubljana, Ljubljana, Slovenia

Correspondence: Danijela Semenič, MD, PhD, Department of Surgical Infections, University Medical Centre Ljubljana, Zaloška cesta 7, 1000 Ljubljana, Slovenia; danijela.semenic@kclj.si

Disclosure: The authors disclose no financial or other conflicts of interest.