Pyoderma Gangrenosum

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 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](B3)

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.