Pyoderma Gangrenosum

Background

Pyoderma gangrenosum is an uncommon, ulcerative cutaneous condition of uncertain etiology. It is associated with systemic diseases in at least 50% of patients who are affected.^{[1, 2]} The diagnosis is made by excluding other causes of similar-appearing cutaneous ulcerations, including infection, malignancy, vasculitis, vasculopathy, venous insufficiency, collagen-vascular diseases, diabetes, and trauma. In a process termed pathergy, new ulcerations may occur after trauma or injury to the skin in 30% of patients who already have pyoderma gangrenosum. (See Presentation, DDx, and Workup.)

Patients with pyoderma gangrenosum may have involvement of other organ systems that manifests as sterile neutrophilic infiltrates. Culture-negative pulmonary infiltrates are the most common extracutaneous manifestation.^{[3, 4]} Other organs systems that may be involved include the heart, the central nervous system, the gastrointestinal (GI) tract, the eyes,^{[5, 6]} the liver, the spleen, the bones, and the lymph nodes. (See Presentation and Workup.)

Therapy for pyoderma gangrenosum involves the use of anti-inflammatory agents, including antibiotics, corticosteroids, immunosuppressive agents, and biologic agents. The prognosis is generally good; however, the disease can recur and residual scarring is common. (See Prognosis, Treatment, and Medication.)

Etiology

The etiology of pyoderma gangrenosum is poorly understood, but dysregulation of the immune system (specifically, altered neutrophil chemotaxis) is believed to be involved.

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Epidemiology

Pyoderma gangrenosum occurs in about 1 in 100,000 persons each year in the United States. Although pyoderma gangrenosum affects both sexes, a slight female predominance may exist.^{[7, 8]}

All ages may be affected by the disease, but it predominantly occurs in the fourth and fifth decades of life. Children account for only 3-4% of the total number of cases. (Nothing is clinically distinctive about pyoderma gangrenosum in children and adolescents other than the age of the patients.)^[9]

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Prognosis

The prognosis of pyoderma gangrenosum is generally good; however, the disease may recur, and residual scarring is common. One study reported that 16% of their 103 patients died during the 8-year study period.^[8] Pain is a common complaint of patients and may require pain medication for control.

Most patients with pyoderma gangrenosum improve with initial immunosuppressive therapy and require minimal care afterwards. However, many patients follow a refractory course, and multiple therapies may fail. These patients pose a difficult clinical problem that requires frequent follow-up and long-term care.

Some patients demonstrate pathergy, or the development of pyoderma gangrenosum–like lesions at the site of skin trauma; in such instances, protection of the skin from trauma may prevent a recurrence of the disease. Pathergy may create problems with wound healing, especially after surgical procedures (eg, breast reconstruction, grafting).^{[10, 11]}

Death from pyoderma gangrenosum is rare, but it may occur due to an associated disease or as a result of therapy.

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History

Patients with pyoderma gangrenosum usually describe the initial lesion as a bite reaction, with a small, red papule or pustule changing into a larger, ulcerative lesion. Others may present with cellulitis or what they think is an abscess. Often, patients give a history of a brown recluse or other spider bite, but they have no evidence that a spider actually caused the initial event.

Pain is the predominant historical complaint. Arthralgias and malaise are often present.

A complete history should be taken with special focus on the organ systems discussed below to determine any underlying systemic disease. Systemic illnesses are seen in 50% of patients with pyoderma gangrenosum and may occur prior to, concurrently with, or following the diagnosis.

Commonly associated diseases include inflammatory bowel disease,^[8] either ulcerative colitis or regional enteritis/Crohn's disease, and a polyarthritis that is usually symmetrical and may be either seronegative or seropositive. Hematologic diseases/disorders are other commonly associated conditions; these include leukemia or preleukemic states, predominantly myelocytic in nature or monoclonal gammopathies (primarily immunoglobulin A [IgA]).^{[8, 12, 13]}

Less commonly associated diseases include other forms of arthritis, such as psoriatic arthritis, osteoarthritis, and spondyloarthropathy; hepatic diseases, including hepatitis and primary biliary cirrhosis; myelomas (IgA type predominantly); and immunologic diseases, such as lupus erythematosus and Sjögren syndrome.^{[14, 15]}

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Physical Examination

Classic pyoderma gangrenosum, as shown in the image below, is characterized by a deep ulceration with a violaceous border that overhangs the ulcer bed. These lesions of pyoderma gangrenosum most commonly occur on the legs, but they may occur anywhere on the body.

View Image

Classic, or typical, pyoderma gangrenosum. This patient did not have an associated disease, and the condition responded well to cyclosporine.

Classic pyoderma gangrenosum may occur around stoma sites; this type, shown in the image below, is known as peristomal pyoderma gangrenosum. It is often mistaken for a wound infection or irritation from the appliance.

View Image

Peristomal pyoderma gangrenosum.

Pyoderma gangrenosum may occur on the genitalia. This form, termed vulvar or penile pyoderma gangrenosum, must be differentiated from sexually transmitted diseases.^[16] One case report describes pyoderma gangrenosum of the scrotum in a patient with Crohn disease.^[17]

Extracutaneous neutrophilic disease may be evident upon ocular examination and has also been reported in the lungs, liver, and bones.^{[4, 14]}

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Approach Considerations

Pyoderma gangrenosum is a diagnosis of exclusion as no specific criteria have been determined to confirm the diagnosis. All other potential causes of similar lesions must be excluded prior to making the diagnosis.

Routine blood work to evaluate for an underlying systemic illness in persons with pyoderma gangrenosum includes a complete blood count (CBC); a comprehensive chemistry profile, including a liver function test; and a urinalysis. In addition, a hepatitis profile should be performed.

Serum and/or urine protein electrophoresis, peripheral smear, and bone marrow aspiration or biopsy should be performed, if indicated, to evaluate for hematologic malignancies.

Other serum studies include a Venereal Disease Research Laboratory (VDRL) test, an antineutrophil cytoplasmic antibody test, a partial thromboplastin time test, and an antiphospholipid antibody test, all of which can help to rule out the following diseases: granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), vasculitis, and antiphospholipid antibody syndrome.

Anti–Saccharomyces cerevisiae antibodies (IgG and IgA) occur in patients with inflammatory bowel disease and might be of value for the identification of an associated disease when there are no bowel symptoms. In addition, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) occur in some patients with  inflammatory bowel disease. c-ANCA should be tested, but is not associated with inflammatory bowel disease and, in an appropriate patient, might lead to a diagnosis of granulomatous polyangiitis. Fecal calprotectin is another test to consider when assessing a patient with pyoderma gangrenosum for associated inflammatory bowel disease.

Serum immunofixation electrophoresis is helpful to determine if a monoclonal gammopathy is present. If it is, it is most frequently an IgA subtype. Myeloma, however, is a rare association.

Cultures

Tissue cultures of the ulcer/erosion for bacteria, fungi, atypical mycobacteria, and viruses are needed. The exact cultures to be performed depend on the individual situation. The cultures should be held for 6 weeks because some of the potential agents may take that long to grow in culture.

Imaging studies

Chest radiography may be performed. Angiography or Doppler studies may be carried out in patients suspected of having arterial or venous insufficiency.

Colonoscopy

Colonoscopy or other tests to exclude associated inflammatory bowel disease or ulcerative colitis may be useful in patients with symptoms. The evaluation of patients with pyoderma gangrenosum and no symptoms of bowel disease is still uncertain.

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Histologic Findings

The histopathologic findings in pyoderma gangrenosum are not specific. However, a biopsy is suggested in almost all instances because it is useful in the exclusion of other diseases, such as infections and malignancy. Microscopic features include massive neutrophilic infiltration, hemorrhage, and necrosis of the overlying epidermis. Histologically, this finding may simulate an abscess or cellulitis, although no organisms are seen and cultures are generally negative or only demonstrate typical skin flora. Neutrophils are often around and within the vessel walls, but the full picture of vasculitis is generally absent.

In early disease, a mixed cell infiltrate may be present. Late in the process, granulation tissue may be present, but granuloma formation is generally believed to be incompatible with the diagnosis of pyoderma gangrenosum.

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Approach Considerations

No specific therapy is uniformly effective for patients with pyoderma gangrenosum. In patients with an associated, underlying disease, effective therapy for the associated condition may be linked to a control of the cutaneous process as well.

Topical therapies include gentle local wound care and dressings, superpotent topical corticosteroids,^[20] cromolyn sodium 2% solution, nitrogen mustard, and 5-aminosalicylic acid. The topical immune modifiers tacrolimus and pimecrolimus may have some benefit in certain patients.^[21]

Systemic therapies include corticosteroids, cyclosporine,^{[22, 23, 24]} mycophenolate mofetil,^{[25, 26, 27]} azathioprine,^[28] dapsone, tacrolimus, cyclophosphamide, chlorambucil,^[29] thalidomide, tumor necrosis factor-alpha (TNF-alpha) inhibitors (eg, thalidomide, etanercept, infliximab, adalimumab,^[30] clofazimine^[31] ), and nicotine.

Intravenous (IV) therapies include pulsed methylprednisolone,^[32] pulsed cyclophosphamide,^[33] infliximab,^{[34, 35, 36, 37]} IV immunoglobulin,^[38] and ustekinumab.^[39] Other therapies include hyperbaric oxygen.^[40]

Canakinumab proved effective in a patient with concomitant hidradenitis suppurativa.^[41]

Other new biologic agents are currently in early trials and may also be helpful for treating pyoderma gangrenosum or other inflammatory conditions. These include the interleukin 23, phosphodiesterase 4 inhibitors, along with the newer Janus kinase inhibitors and intravenous immune globulin. All have case reports demonstrating benefit.^{[42, 43, 44]}  

Surgery

Surgery should be avoided, if possible, because of the pathergic phenomenon that may occur with surgical manipulation or grafting, resulting in wound enlargement.^[45] Pathergy is seen in about 30% of cases. In some patients, grafting has resulted in the development of pyoderma gangrenosum at the harvest site. In cases in which surgery or superficial debridement is required, the best plan, if possible, is to have the patient on therapy, and active disease under control, in order to prevent the development of new pyoderma gangrenosum lesions.^[46]

Some patients with ulcerative colitis have responded to total colectomy; in other patients, however, the disease is peristomal and occurs following bowel resection.

Transfer

Care of the patient with pyoderma gangrenosum is often referred from the general dermatologist to tertiary centers where such patients are seen more frequently.

Follow-up

Patients with pyoderma gangrenosum should receive follow-up care on a regular basis to monitor drug therapy and to measure the size of the lesion or lesions. Multiple methods of wound care are available.

Activity

Patients should maintain their range of motion and perform all activities that they are able to tolerate.

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Consultations

Working with the primary care physician is wise for all patients. Depending on patient findings, however, other specialists may need to be consulted, including the following:

• Gastroenterologist or GI surgeon, proctorectal surgeon, or general surgeon - For patients with inflammatory bowel disease
• Rheumatologist - For patients with arthritis
• Ophthalmologist - If ocular disease is present
• Hematologist/oncologist - When preleukemia, leukemia, monoclonal gammopathy, or other neoplasm is associated
• Plastic surgeon or general surgeon - When debridement or grafting is deemed necessary, but again should be performed with caution or while on appropriate therapy, to prevent the potential for pathergy

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Medication Summary

Therapy with corticosteroids—such as the glucocorticoid prednisone—is often initially prescribed. An immunosuppressive agent is also sometimes initiated, either later or simultaneously; this is particularly the case in patients for whom high-dose, long-term therapy is anticipated. Some physicians select cyclosporine as the initial therapy. Other immunosuppressives used in treatment include azathioprine, mycophenolate, cyclophosphamide, chlorambucil, and tacrolimus.

The TNF-alpha inhibitors—which include thalidomide, etanercept, infliximab, adalimumab, certolizumab,^[47] golimumab, and clofazimine—are close to first-line agents in the treatment of pyoderma gangrenosum.

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Prednisone

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is considered the drug of choice. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. Methylprednisolone IV may be used in some patients.

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Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

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Cyclosporine (Sandimmune, Neoral, Gengraf)

• Dosing, Interactions, etc.

Clinical Context:  Cyclosporine has been demonstrated to be helpful in a variety of skin disorders. An effective steroid-sparing agent, it has also been used as primary therapy in some patients.

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Azathioprine (Imuran, Azasan)

• Dosing, Interactions, etc.

Clinical Context:  Azathioprine is another drug that may be effective as a steroid-sparing agent. It antagonizes purine metabolism and inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Azathioprine may decrease the proliferation of immune cells, which results in lower autoimmune activity.

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Mycophenolate (CellCept, Myfortic)

• Dosing, Interactions, etc.

Clinical Context:  Mycophenolate inhibits purine synthesis and the proliferation of human lymphocytes. It may be used as a steroid-sparing agent or as a primary agent in patients who do not respond to first-line agents.

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Cyclophosphamide

• Dosing, Interactions, etc.

Clinical Context:  Cyclophosphamide is an alkylating agent that depresses B-cell and T-cell function. It is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

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Chlorambucil (Leukeran)

• Dosing, Interactions, etc.

Clinical Context:  Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription. It is used as a primary or steroid-sparing agent.

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Tacrolimus (Prograf, Hecoria)

• Dosing, Interactions, etc.

Clinical Context:  Tacrolimus suppresses humoral immunity (T-lymphocyte) activity.

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Class Summary

These agents have immunomodulatory effects.

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IV immunoglobulins (Octagam, Hizentra, Gammagard, Gamunex)

• Dosing, Interactions, etc.

Clinical Context:  IV immunoglobulin neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including interferon (INF)-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; and promotes remyelination. It may increase cerebrospinal fluid (CSF) IgG (10%).

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Class Summary

These agents are used to improve the clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.

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Infliximab (Remicade)

• Dosing, Interactions, etc.

Clinical Context:  Infliximab is a chimeric IgG1k monoclonal antibody that neutralizes the cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. The drug reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas.

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Adalimumab (Humira)

• Dosing, Interactions, etc.

Clinical Context:  Adalimumab is a TNF-alpha inhibitor. It is a fully human inhibitor of TNF-alpha that is administered by subcutaneous (SC) injection.

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Etanercept (Enbrel)

• Dosing, Interactions, etc.

Clinical Context:  Etanercept is a soluble p75 TNF-receptor fusion protein (sTNFR-Ig). It inhibits TNF binding to cell surface receptors, thereby decreasing inflammatory and immune responses.

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Golimumab (Simponi)

• Dosing, Interactions, etc.

Clinical Context:  Golimumab is a tumor necrosis factor (TNF)–alpha inhibitor. It decreases inflammation caused by overproduction of TNF associated with chronic inflammatory diseases. It is a fully human inhibitor of TNF-alpha that is administered by subcutaneous (SC) injection.

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Certolizumab pegol (Cimzia)

• Dosing, Interactions, etc.

Clinical Context:  Certolizumab pegol is a pegylated antitumor necrosis factor (TNF)–alpha blocker, which results in disruption of the inflammatory process. It is a fully human inhibitor of TNF-alpha that is administered by subcutaneous (SC) injection.

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Ustekinumab (Stelara)

• Dosing, Interactions, etc.

Clinical Context:  Ustekinumab is a human monoclonal antibody directed against IL-12 and IL-23, thereby interfering with T-cell differentiation and activation and subsequent cytokine cascades. It is indicated for moderate-to-severe plaque psoriasis and has been used successfully in pyoderma gangrenosum.

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Thalidomide (Thalomid)

• Dosing, Interactions, etc.

Clinical Context:  Thalidomide is an immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. In patients less than 50 kg (110 lb), start at the low end of the dose regimen.

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Clofazimine (Lamprene)

• Dosing, Interactions, etc.

Clinical Context:  Clofazimine inhibits mycobacterial growth, binding preferentially to mycobacterial DNA. It has antimicrobial properties, but its mechanism of action is unknown.

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Class Summary

These agents have effects on the activity of the immune system. In current practice, TNF inhibitors are close to first-line treatment.

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