Pyoderma Gangrenosum


Article Author:
Shawn Schmieder


Article Editor:
Karthik Krishnamurthy


Editors In Chief:
Dustin Constant
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Radia Jamil
Patrick Le
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Anoosh Zafar Gondal
Saad Nazir
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Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/28/2019 10:14:01 PM

Introduction

Pyoderma gangrenosum is an ulcerative disorder that falls into the category of neutrophilic dermatoses. Pyoderma gangrenosum should not be confused with pyogenic granuloma, a completely separate entity but with an equally ill-fitting name. Despite its name, pyoderma gangrenosum is not caused by infection or gangrene. Pyogenic granuloma is often associated with systemic disease.  The diagnosis is made clinically after excluding other similar skin disorders.[1][2][3]

Etiology

The most common associated systemic disorders include rheumatoid arthritis, inflammatory bowel disease, and other autoimmune and inflammatory conditions. In addition, pyoderma gangrenosum has an association with both solid tumors and hematologic malignancies. Pyoderma gangrenosum is associated with ulcerative colitis in 5% to 12% of cases and is associated with Crohn disease in 1% to 2% of cases. It is not clear if the development of pyoderma gangrenosum correlates with severity or flares of inflammatory bowel disease. Furthermore, pyoderma gangrenosum does not always resolve when the associated bowel disease is treated. In a study of 103 patients with pyoderma gangrenosum, 20% of the patients had hematologic disorders, and 19% of the patients had seronegative arthritis. [4][5][6]

Epidemiology

It is estimated that less than 5% of cases occur in children. The age range for the development of the disease is from about 11 to 89 years of age.

Pathophysiology

The pathogenesis of pyoderma gangrenosum is not fully understood. It is thought to involve genetic mutations, neutrophil dysfunction, and immune/inflammatory dysregulation. Some lesions of pyoderma gangrenosum have been found to have a proliferation of clonal T-cells. In addition, inflammasomes have been postulated to be involved in the neutrophil chemotaxis that occurs in these lesions. Inflammasomes are complexes of receptors that are part of innate immune system signaling. Some cases of pyoderma gangrenosum are associated with a mutation in Janus kinase 2, which is involved in the production of several cytokines. Abnormal cytokine signaling by T cells and macrophages is likely a component of the disease process. Lesions of pyoderma gangrenosum have been found to have increased levels of inflammatory mediators. For example, IL-23 has been found to be increased in lesions of pyoderma gangrenosum. IL-23 is important in activating neutrophils and stimulating IL-17 mediated inflammation.[7]

Histopathology

The disease is a clinical and histologic diagnosis of exclusion as the histologic features are non-specific. The goal of the biopsy is to exclude other causes of ulceration. Early lesions of pyoderma gangrenosum should show an infiltrate of neutrophils in the dermis. Lesions may demonstrate necrotic dermal vessels. Direct immunofluorescence of biopsy specimens of pyoderma gangrenosum is nonspecific.

History and Physical

Some of the clinical variants of pyoderma gangrenosum include vesicular-bullous, pustular, ulcerative, and superficial granulomatous forms. The vesicular-bullous variant appears on the upper extremities and face and has overlap with another neutrophilic disorder, Sweet syndrome. There can be systemic symptoms including fever and joint pain. The pustular type of pyoderma gangrenosum features many small pustules. These pustules may either resolve or develop into ulcers. This variant is associated with inflammatory bowel disease. In addition to these variants, pyoderma gangrenosum can present as a vegetative form. Certain, less common, sites of involvement, such as the vulva and peristomal area, can be very resistant to treatment. Patients often experience pain associated with the lesions that may be out of proportion to the size of the ulcer. Lesions of pyoderma gangrenosum usually heal with a cribriform scar.

One of the most important features of the disease is a phenomenon known as pathergy. Pathergy is defined as an exaggerated response to a minor skin injury or worsening of an existing wound with minimal insult or trauma. This has a wide array of implications for the patient including debridement and simple wound care. This also makes the decision to perform certain surgeries and procedures much more difficult. Lastly, insults to the skin that would be nearly meaningless for most people can be devastating for some patients with pyoderma gangrenosum.

Evaluation

As mentioned, pyoderma gangrenosum is a diagnosis of exclusion both clinically and histologically. In addition to nonspecific histologic features, there are no specific lab markers that aid in its diagnosis.[8][9][10]

In 2004, diagnostic criteria were proposed but have not been confirmed. According to this proposal, both major criteria and two of the minor criteria are required to make the diagnosis.

Major Criteria 

  • Rapid progression of a painful, necrolytic cutaneous ulcer with an irregular, violaceous, and undermined border
  • Other causes of cutaneous ulceration have been excluded

Minor Criteria 

  • History suggestive of pathergy or cribriform scarring
  • Systemic diseases associated with pyoderma gangrenosum
  • Histopathologic findings (sterile dermal neutrophilia, +/- mixed inflammation,  +/-  lymphocytic vasculitis)
  • Treatment response (rapid response to systemic steroid treatment)

A number of syndromes include pyoderma gangrenosum in the clinical criteria and are named with acronyms for these criteria. These include syndromes like PAPA syndrome which includes pyoderma gangrenosum, acne, and pyogenic sterile arthritis and PASH syndrome which includes pyoderma gangrenosum, acne, and hidradenitis suppurativa. A helpful way to organize these disorders is by remembering that they all include pyoderma gangrenosum and acne but are distinguished by the addition of hidradenitis suppurativa, colitis, and certain types of arthritis. These disorders share the common factor of immune system dysregulation with aberrant interleukin-1 signaling.

The pathergy skin test involves poking the skin and observing for an exaggerated reaction.

Treatment / Management

If present, the underlying systemic disease must be treated, but there is not an accepted correlation between the underlying systemic disease severity and the severity of pyoderma gangrenosum.[11][2]

The use of systemic immunosuppression is determined by how fast the disease progresses. If the size of the lesion is rapidly growing, systemic medications like corticosteroids or cyclosporine may be used. The STOP GAP randomized control trial in 2015 compared oral prednisolone and oral cyclosporine in the treatment of pyoderma gangrenosum. The results did not show a significant difference in the speed of lesion healing with either medication. At six months, 47% of patients on cyclosporine had healed ulcers, and 47% of the patients on prednisolone had healed ulcers. Recurrence was similar among the two groups as were adverse reactions. However, serious adverse reactions such as infections were more common in the patients receiving prednisolone.

If a patient has a history of pyoderma gangrenosum, especially aggressive pyoderma gangrenosum, some physicians will use immunosuppressant drugs prophylactically before surgery to prevent the formation of pyoderma gangrenosum. One such regimen consists of methylprednisolone and cyclosporine combined. Obviously, avoiding unnecessary surgery or procedures is essential.[12]

For more indolent or limited disease, topical or intralesional therapy alone may be sufficient. Topical and intralesional steroids, as well as topical tacrolimus, have been used with success. Other agents that have been tried are nicotine, topical dapsone, and sodium cromoglycate.

Wound care and pain control are key features in the treatment of pyoderma gangrenosum. Patients and healthcare providers must cleanse the wound to prevent infection. Debridement is important but must be performed very cautiously to ensure that only nonviable tissue is removed because of the aforementioned association with pathergy. 

Other therapies that have been successful are anti-TNF-alpha drugs such as etanercept and adalimumab. Ustekinumab, an IL-12/23 inhibitor used in the treatment of psoriasis, has been reported to improve pyoderma gangrenosum. Other therapies that may be effective in the treatment of pyoderma gangrenosum include Canakinumab, an IL-1 beta monoclonal antibody, and tocilizumab, an anti IL-6 monoclonal antibody.

Differential Diagnosis

The differential diagnosis includes infectious diseases like mycobacterial infection and deep fungal infections. Also included in the differential are noninfectious diseases such as iododerma or bromoderma. Other causes of ulcers to consider are arterial ulcers and Martorell ulcers. Arterial ulcers may have associated weakened pulses on the corresponding anatomical side.

Enhancing Healthcare Team Outcomes

The treatment of pyoderma gangrenosum requires a multidisciplinary approach. The skin lesions take a long time to heal, frequently breakdown despite adequate treatment and are very painful. Besides the physician, a wound care nurse is necessary. The wound care nurse has to educate the patient on adequate wound management, avoidance of trauma and also maintain physical activity. The pharmacist should encourage the patient to avoid smoking and be compliant with the medications, as relapses are common.  Because the pain is often severe, prescription strength narcotics are often required but these drugs should be tapered quickly to avoid physical dependence. A pain consult should be made to help manage the pain without narcotics. All patients should be told to avoid surgery as this often results in poor wound healing and development of pathergy.[13][14] (Level V)

Outcomes

In the majority of patients, the prognosis is good but the skin disorder does recur. In addition, most people are left some residual scar. The acute disorder is also associated with moderate-to-severe pain that often requires prescription strength narcotics. Despite the use of immunosuppressive agents, relapses are common and long-term care is required. The skin lesions breakdown from minimal trauma. [15][16](level V)


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Pyoderma Gangrenosum - Questions

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Which of the following is false about pyoderma gangrenosum (PG)?

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Which of the following are the features of PAPA syndrome?



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A patient presents with a wound on her left lower extremity that does not heal despite wound care and antibiotics. It started as a painful papule and then ulcerated. The patient thought it was a spider bite. The wound has overhanging violaceous borders. Debridement worsens the condition. What is the next step in diagnosis?



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A 55-year-old female with a past medical history of Crohn disease and hypertension presents to your clinic with a non healing wound on her lateral lower leg that has been present for about 2 months and rapidly expanding. On exam the ulcer is about 4 cm. The wound did not heal after two courses of antibiotics given to her by her primary care physician. Bacterial culture is negative. The lesion is biopsied and sent tissue for fungal culture and for histopathologic analysis. Culture is negative and the pathology report shows a nonspecific neutrophilic infiltrate in the dermis. Vascular evaluation is negative for both venous and arterial disease. The patient recently had routine labs drawn with her primary care physician. Her CBC and comprehensive metabolic profile are unremarkable and her hemoglobin A1c was 5.5%. You diagnose the patient with pyoderma gangrenosum. The patient reports she has been researching the disease and asks if cyclosporine is more effective than prednisolone in the treatment of this disease. What can she be told based on the recent STOP GAP trial?



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A 45-year-old male with a known history of pyoderma gangrenosum presents with a lower extremity ulcer that has been present for about 6 weeks. He reports that he cut his leg on the edge of a table about two months ago and reports the wound never healed but instead became "larger and deeper." You suspect that this new ulcer is another lesion of pyoderma gangrenosum. What phenomenon is the patient describing?



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A 65-year-old woman with a past medical history of diabetes mellitus and ulcerative colitis presents with a non-healing ulcer on her medial lower right leg. While forming your differential, pyoderma gangrenosum is considered because of the patient's history of inflammatory bowel disease. How is pyoderma gangrenosum diagnosed?



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A 64-year-old woman with past medical history of diabetes mellitus and ulcerative colitis presents to your clinic with a non-healing ulcer on her lower right leg. While forming the differential, pyoderma gangrenosum is likely because of the patient's medical history. How is pyoderma gangrenosum diagnosed?



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A 45-year-old male presents with a report of a rapidly progressive ulcer on his right lower leg. On exam, there is a 3 cm ulcer on the patient’s right leg with some purulence over the center of the lesion. The patient is referred to wound care and workup initiated. After excluding other causes of lower extremity ulceration, the patient is diagnosed with pyoderma gangrenosum. The lesion seems to be progressing despite excellent wound care and now measures 4 cm. What is the next best step in the treatment of this disease?



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A 38-year-old woman with past medical history of Crohn disease and pyoderma gangrenosum presents to for further treatment of pyoderma gangrenosum. She asks if her pyoderma gangrenosum is in anyway related to her Crohn disease. What should she be told?



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Pyoderma Gangrenosum - References

References

Simpson AM,Chen K,Bohnsack JF,Lamont MN,Siddiqi FA,Gociman B, Pyoderma Gangrenosum-like Wounds in Leukocyte Adhesion Deficiency: Case Report and Review of Literature. Plastic and reconstructive surgery. Global open. 2018 Aug     [PubMed]
Abdul-Fattah B,Al-Muriesh M,Huang CZ, Efficacy of topical calcineurin inhibitors in pyoderma gangrenosum. Dermatologic therapy. 2018 Sep 25     [PubMed]
Skok P,Kristijan S, Acute febrile neutrophilic dermatosis in a patient with Crohn's disease: case report and review of the literature. Acta dermatovenerologica Alpina, Pannonica, et Adriatica. 2018 Sep     [PubMed]
Yamamoto T, Epidemiology of pyoderma gangrenosum in Japanese patients by questionnaire survey. The Journal of dermatology. 2018 Sep 19     [PubMed]
Brambilla L,Minuti A,Brambilla M,Tourlaki A,Genovese G,Berti E, Late-onset post-mammoplasty pyoderma gangrenosum treated with tobacco-pouch suture combined with oral corticosteroids. Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia. 2018 Sep 18     [PubMed]
Martinez-Rios C,Jariwala MP,Highmore K,Duffy KW,Spiegel L,Laxer RM,Stimec J, Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature. Pediatric radiology. 2018 Sep 17     [PubMed]
Genovese G,Tavecchio S,Berti E,Rongioletti F,Marzano AV, Pyoderma gangrenosum-like ulcerations in granulomatosis with polyangiitis: two cases and literature review. Rheumatology international. 2018 Jun     [PubMed]
Lopez Pineiro M,Willis E,Yao C,Chon SY, Pyoderma gangrenosum-like ulceration of the lower extremity secondary to sunitinib therapy: a case report. SAGE open medical case reports. 2018     [PubMed]
Ashchyan HJ,Butler DC,Nelson CA,Noe MH,Tsiaras WG,Lockwood SJ,James WD,Micheletti RG,Rosenbach M,Mostaghimi A, The Association of Age With Clinical Presentation and Comorbidities of Pyoderma Gangrenosum. JAMA dermatology. 2018 Apr 1     [PubMed]
Vaysse-Vic M,Mathieu PA,Charissoux A,Charissoux JL,Marcheix PS, Pyoderma gangrenosum or necrotising fasciitis? Diagnostic and therapeutic wanderings. Orthopaedics     [PubMed]
Saffie MG,Shroff A, A Case of Pyoderma Gangrenosum Misdiagnosed as Necrotizing Infection: A Potential Diagnostic Catastrophe. Case reports in infectious diseases. 2018     [PubMed]
McKenzie F,Cash D,Gupta A,Cummings LW,Ortega-Loayza AG, Biologic and small-molecule medications in the management of pyoderma gangrenosum. The Journal of dermatological treatment. 2018 Sep 7     [PubMed]
Bissonnette C,Kauzman A,Mainville GN, Oral Pyoderma Gangrenosum: Diagnosis, Treatment and Challenges: A Systematic Review. Head and neck pathology. 2017 Dec     [PubMed]
Pichler M,Larcher L,Holzer M,Exler G,Thuile T,Gatscher B,Tappeiner L,Deluca J,Carriere C,Nguyen VA,Moosbrugger-Martinz V,Schmuth M,Klein GF,Eisendle K, Surgical treatment of pyoderma gangrenosum with negative pressure wound therapy and split thickness skin grafting under adequate immunosuppression is a valuable treatment option: Case series of 15 patients. Journal of the American Academy of Dermatology. 2016 Apr     [PubMed]
Partridge ACR,Bai JW,Rosen CF,Walsh SR,Gulliver WP,Fleming P, Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic review of observational studies and clinical trials. The British journal of dermatology. 2018 Aug     [PubMed]
Kaffenberger BH,Hinton A,Krishna SG, The impact of underlying disease state on outcomes in patients with pyoderma gangrenosum: A national survey. Journal of the American Academy of Dermatology. 2018 Oct     [PubMed]

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