Surgical Management of Lower Extremity Pyoderma Gangrenosum With Viable Cryopreserved Umbilical Tissue: A Case Series

Pyoderma gangrenosum (PG) is a rare skin disease that often presents as a uniquely painful and necrotic ulceration of the lower extremity. Histologically, it is characterized by an increased number of neutrophils in the dermis in the absence of infection.^1,2 About half of PG cases are associated with systemic diseases, such as inflammatory bowel disease, polyarthritis, and hematologic disorders.³ The pathogenesis of PG remains poorly understood, but it is thought to be a multifactorial combination of neutrophil dysfunction, inflammatory mediators, and genetic predisposition.⁴ This supports the theory that PG is a hyperreactive response to inflammation and trauma in predisposed patients.⁵ Currently, there are no specific lab tests or histopathologic exams to confirm PG, and it is usually a diagnosis of exclusion.⁶ As many as 10% of PG cases may be misdiagnosed, with mimickers including vascular occlusive disease or venous disease, vasculitis, cancer, primary infection, necrotizing fasciitis, exogenous tissue injury, or other inflammatory diseases.⁵ The misdiagnosis of PG can have grave consequences, because treatment intended for PG with high-dose prednisone or immunosuppressive medications may be contraindicated in patients with diseases that may produce ulceration-mimicking PG, such as an infectious or malignant process.⁷

There is no gold standard treatment for PG, and it can be difficult to manage.^8-10 The management goals are to control local and systemic inflammation and improve wound healing. Most treatment regimens involve both topical and systemic immunosuppressants with appropriate wound care and pain management.¹¹ Commonly used agents include systemic corticosteroids, cyclosporine, infliximab, and canakinumab, primarily targeting the inflammatory response.¹² Recently, tumor necrosis factor alpha inhibitors have been used for refractory PG.^8,13,14 Initial improvement of ulcers may occur within days of starting treatment, but complete ulcer healing often requires weeks to months.^8,13,14 Therefore, there remains a high rate of nonresponse and recurrence.

Surgical management of PG ulcers is divisive, with 25% to 50% of these cases potentially exhibiting pathergy in which a minor trauma can lead to the development of ulcers that may be resistant to healing.¹⁵ Pyoderma gangrenosum ulcers can be aggravated by surgery, which is often a hallmark when considering the diagnosis of PG. Pathergy may be mediated by ensuring the patient’s PG is clinically dormant prior to surgery.^16,17 Select literature supports surgical intervention in conjunction with medical management in the forms of free-flaps, split-thickness skin grafts, and cultured keratinocyte autografts.^18-20

Advanced wound care products such as cellular- and/or tissue-based products are effective in helping stagnant chronic wounds reach full closure. The benefits of using human placental tissues in tissue regeneration are now well documented.^21,22 Optimally preserved placental membranes are of particular interest, as they contain a combination of growth factors and extracellular matrices as well as viable mesenchymal stem cells, fibroblasts, and epithelial cells. These components have been shown to decrease inflammation,²³ lower microbial loads,²⁴ and promote tissue regeneration.²⁵ Furthermore, amnion/chorion-based skin substitutes that have been cryopreserved and contain viable cells have been shown to promote more cell recruitment and reduce inflammation better than devitalized placental membranes.^26,27 This consecutive case series presents evidence of using a cryopreserved umbilical cord tissue with living cells in treating patients diagnosed with PG.

All 3 patients had a chronic wound, a diagnosis of PG, and failed standard of care (SOC) treatments. They then were treated with either 1 or 2 applications of viable cryopreserved umbilical tissue allograft (vCUT; Stravix; Osiris Therapeutics, Inc, Columbia, MD) that were applied to the patients’ chronic wounds in accordance with the manufacturer’s guidelines, followed by standard of care for the specific wound. Each wound area was serially photographed and measured at subsequent office visits.

Case 1
A 61-year-old woman, with a past medical history of allergic rhinitis, underwent a standard bunionectomy with screw fixation without any intraoperative issues. At 4-days postoperatively, she developed a fever of 100.7°F despite being on per-protocol prophylactic 500 mg of oral cephalexin 3 times daily for 1 week, while noticing increasing pain at the procedure site. At 6-days postop in the surgeon’s office, the incision was evaluated, and drained, and the wound culture was sent. She was immediately admitted to the emergency department with an elevated temperature of 102.5°F and initial white blood cell (WBC) count of 14 900, with neutrophils 82%. A formal incision and drainage (I&D) in the operating room (OR) was performed the same evening for suspected infection and abscess. She was started on 1 g of vancomycin every 24 hours and 3.375 g of piperacillin/tazobactam every 6 hours after the procedure, and an infectious disease consultation was ordered.

The patient continued to experience pain and elevated temperatures after the initial I&D, and surrounding skin necrosis formed shortly after. She underwent a subsequent washout and debridement 2 days later, in which all necrotic tissue was removed, multiple deep tissue and wound cultures were taken, and negative pressure wound therapy (NPWT) at 125 mm Hg continuous pressure was applied. In addition, 600 mg of intravenous (IV) clindamycin administered every 8 hours was added to the antibiotic regimen. Following the procedure, she still remained febrile to 102.4°F with a WBC of 13 800 and neutrophils 77%. As she was not improving clinically and her wound continued to worsen, concern developed for a necrotizing infection. The patient underwent a third surgical debridement, with cyanotic changes noted to the hallux. Cultures were taken at that point as well.

At this time, multiple wound and tissue cultures obtained from the office and OR did not grow any microbes. Surgical pathology showed gangrenous necrosis with abscess. There was now suspicion of PG, given her worsening clinical picture despite multiple debridement and antibiotic coverage, negative cultures, increasing leukocytosis to 22 300, and neutrophilia at 90%. Dermatology was consulted and agreed with the working diagnosis of PG in light of the aforementioned findings. The patient then was started on 60 mg of methylprednisolone daily. Rheumatology also was consulted for evaluation of a possible underlying autoimmune/vasculitic etiology. A full workup followed, with all rheumatologic serologies being negative. Serial radiographic images showed no concern for acute osteomyelitis and intraoperative examination of the osteotomy, and fixation was deemed very stable, thus the hardware was not removed.

The patient failed to show significant improvement despite high-dose (60 mg) IV methylprednisolone every 24 hours, with a WBC of 21 750 and consistent neutrophilia in the 90%. She was transitioned to infliximab infusions 5 mg/kg on weeks 0, 2, 6, and 8 and with low-dose (5 mg) methotrexate weekly for 8 weeks with low-dose methotrexate for 6 months, as these agents have a more acceptable side effect profile.¹² During the following daily inpatient clinical exams, the ulcer demonstrated increased granulation without purulence. She was discharged to a rehabilitation facility with continued infliximab infusions with low-dose methotrexate as per the aforementioned schedule. 

A multidisciplinary decision was reached to apply a vCUT allograft to the wound bed. The patient demonstrated continued clinical improvement with decreased pain, and the ulcer completely closed with SOC with nonadhesive dressings and hydrogel. The cyanotic changes to the hallux also improved greatly and did not require any further surgical intervention or amputation. Complete time to total healing was about 7 months after initial presentation (Figure 1).

Case 2
A 73-year-old man with a past medical history of hypertension, mantle cell lymphoma of the lacrimal gland (treated with chemotherapy and bone marrow transplantation), and prostate cancer was evaluated for a chronic, nonhealing ulcer of the right anterior tibia. The wound was present for 6 months, was increasing in size, and had failed conservative topical care with antibiotic ointment. A diagnosis of PG was confirmed via biopsy at an outside facility prior to referral. The patient had a history of infection to the area that was treated with IV antibiotics. He also was referred to vascular surgery for testing, which provided a benign vascular exam.

On initial physical exam, the ulcer was a Wagner Grade 1/2, measuring 3.5 cm x 3.0 cm x 0.3 cm. The patient was scheduled for debridement in the OR, application of vCUT allograft, and application of NPWT at 125 mm Hg continuous pressure, which was performed without complication. Surgical pathology yielded granulation tissue. At the 1-week postop exam, the ulcer was a Grade 1, measuring 2.5 cm x 2.5 cm x 0.1cm, with granulation and contraction of the wound periphery noted. Negative pressure wound therapy was continued for 3 weeks. Upon discontinuation of NPWT, local wound care was continued with hydrogel and dry sterile dressings. He was followed in the office monthly with continued granulation and contraction noted. About 20-weeks postop, the ulcer measured 0.5 cm x 0.5 cm x 0.0 cm. At 8-months postop, the ulcer had fully healed (Figure 2). 

Case 3
A 55-year old woman with a past medical history of type 2 diabetes presented with a biopsy-confirmed, nonhealing PG ulcer of the right dorsal forefoot that had been present for 1 year. Previous physicians had offered her a transmetatarsal amputation, but she wanted an alternative solution. At the time of original presentation, she had palpable pedal pulses, an elevated WBC of 14 000, normal temperature, C-reactive protein (CRP) of 15.2, and hemoglobin A_1C of 9.8%. The ulcer measured 7.5 cm x 5.5 cm in diameter and extended to the level of tendon and bone. An x-ray could not rule out bone infection. Debridement of necrotic tissue and tendons was performed in the OR, in addition to a bone biopsy. A bilayer matrix dressing (Integra Bilayer Wound Matrix; Integra LifeSciences, Inc, Plainsboro, NJ) was applied under close follow-up with the infectious disease team. The bone biopsy was positive for osteomyelitis, and she was treated with 6 weeks of 3.375 g of IV piperacillin/tazobactam every 8 hours via a peripherally inserted central catheter line. Clinical improvement was noted when the silicone top-layer was removed 4 weeks after surgery, with a repeat CRP value of 2. The wound stalled at a size of 4.0 cm x 2.0 cm with mixed granular/fibrotic tissue. 

At 8 weeks following index surgery, vCUT was applied in the OR in conjunction with a NPWT dressing. The patient soon developed a PG flare-up, and rheumatology started her on 60 mg of oral methylprednisolone daily. Subsequently, the wound size increased, became infected, and the graft was deemed nonviable. After consultation with rheumatology, the steroids were stopped, and the patient was started on methotrexate. She began a 6-week course of 300 mg of oral clindamycin every 8 hours after a deep tissue culture was performed. After 3 months, a second application of vCUT under a NPWT dressing was applied. 

Six weeks after the second vCUT application, the ulcer demonstrated granulation tissue, decreased in size to 2.0 cm x 1.0 cm with minimal depth, and was treated with SOC until full epithelialization occurred. Total time to healing was 21 months from initial presentation (Figure 3). The patient is working full-time and ambulating in a diabetic shoe at the time of this publication. 

Pyoderma gangrenosum is an idiopathic, inflammatory, ulcerative condition with a poorly understood pathogenesis. There is no gold standard treatment for PG, and it can be difficult to manage. Most treatment regimens involve both topical and systemic immunosuppressants with appropriate wound care and pain management. Surgical intervention is decided on a case-by-case basis and, for difficult or refractory cases, is done in conjunction with strict medical management.^6,7,9

While most reported studies^13,22 have been on diabetic and venous leg ulcers, amniotic membranes (eg, vCUT) also have been shown to be effective in other types of chronic wounds, including PG. In a study by Gruss and Jirsch,²⁸ the authors treated a patient who developed PG after a total proctocolectomy for Crohn’s disease and was completely resistant to all forms of treatment for 18 months. Treatment with placental membrane relieved the patient’s pain; within 6 weeks, the wound reduced in size by 66%. In another study,¹⁹ a cryopreserved placental membrane was used to treat a 68-year-old patient with a history of lymphedema, diabetes, venous insufficiency, and a recurrent PG ulcer with an area of 115 cm². At the time of that publication, the ulcer achieved 64% closure after 9 weekly applications, and treatment was ongoing.¹⁹ 

The present study reports treating a consecutive series of patients diagnosed with PG with a cryopreserved umbilical cord tissue with living cells. While umbilical cord and placental membranes both have mesenchymal stem cells, which are well known to have immunosuppressive^26,29-32 and antimicrobial properties,^33-35 umbilical cord is also a rich source of high molecular weight hyaluronic acid (HC-HA) and pentraxin 3 (PTX3). The HC-HA/PTX3 has a unique ability to promote the death of activated macrophages while downregulating pro-inflammatory cytokines and upregulating anti-inflammatory cytokines.^36-40 In addition, umbilical cord tissue is thicker and can be sutured, which may provide an advantage for application on deeper wounds.

The limitations of this type of study include limited sample size and difficulty in diagnosing PG. Not all PG ulcers are amenable to surgery, but in those that are, vCUT may be a viable option for wound coverage.

In cases in which nonoperative management of PG does not improve the lesions alone, surgical management may need to be employed. The present report presents 3 different clinical scenarios of lower extremity PG that underwent treatment with vCUT and resulted in complete healing. To the best of the authors’ knowledge, this is the first case series demonstrating the ability of vCUT to heal these difficult-to-treat ulcers. In addition, it may be an effective modality to adjunctive management of PG. 

Authors: Robert Fridman, DPM, FACFAS, CWSP¹; Tzvi Bar-David, DPM, FACFAS¹; Joseph Larsen, DPM, FACFAS²; and Andrew R. Olson, DPM³

Affiliations: ¹Columbia University Medical Center, New York, NY; ²ProHealth Care, New Hyde Park, NY; and ³New York-Presbyterian Queens, Flushing, NY

Correspondence: Robert Fridman, DPM, FACFAS, CWSP, 60 East 56th Street, New York, NY 10022; rfridmandpm@aol.com; rf2256@cumc.columbia.edu 

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