Pyoderma Gangrenosum

Background

Pyoderma gangrenosum is an uncommon ulcerative cutaneous condition whose cause is uncertain. Although the etiology of this condition is poorly understood, dysregulation of the immune system (specifically, altered neutrophil chemotaxis) is believed to be involved. Pyoderma gangrenosum is associated with systemic diseases in at least 50% of patients who are affected.^{[1, 2, 3]}

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.^{[4, 5]} Other organ systems that may be involved include the heart, the central nervous system (CNS), the gastrointestinal (GI) tract, the eyes, 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.)

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Epidemiology

Pyoderma gangrenosum occurs in about 1 in 100,000 persons each year in the United States. A Spanish study that examined hospital admissions for pyoderma gangrenosum as a percentage of total hospital admissions over the period 1999-2021 found that in 2021, pyoderma gangrenosum admissions accounted for 91.9 of every 1,000,000 admissions.^[6]

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. Although this condition is known to affect both sexes, a slight female predominance may exist.^{[7, 8, 6]}

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Prognosis

The prognosis for patients with 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 patient complaint 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 necessitates 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 or grafting).^{[9, 10]}

Death from pyoderma gangrenosum is rare, but it may occur as a consequence of 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 evolving 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 whether an underlying systemic disease is present. Systemic illnesses are seen in 50% of patients with pyoderma gangrenosum and may occur before, concurrently with, or after the diagnosis.

Commonly associated diseases include inflammatory bowel disease (IBD)^[8]  (either ulcerative colitis or regional enteritis/Crohn disease) and a polyarthritis that is usually symmetrical and may be either seronegative or seropositive. Hematologic disorders are other commonly associated conditions; these include leukemia or preleukemic states, predominantly myelocytic in nature or monoclonal gammopathies (primarily involving immunoglobulin A [IgA]).^{[8, 11, 12]}

Less commonly associated diseases include other forms of arthritis (eg, psoriatic arthritis, osteoarthritis, and spondyloarthropathy), hepatic diseases (eg, hepatitis and primary biliary cirrhosis), myelomas (predominantly IgA type^[13] ), and immunologic diseases (eg, lupus erythematosus and Sjögren syndrome).

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Physical Examination

Classic pyoderma gangrenosum (see the image below) is characterized by a deep ulceration with a violaceous border that overhangs the ulcer bed. These lesions most commonly occur on the legs but may occur anywhere on the body.

View Image

Classic, or typical, pyoderma gangrenosum. No associated disease was present, and condition responded well to cyclosporine.

Classic pyoderma gangrenosum may occur around stoma sites; this type is known as peristomal pyoderma gangrenosum (see the image below).^[14] 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. One case report described pyoderma gangrenosum of the scrotum in a patient with Crohn disease.^[15]

Extracutaneous neutrophilic disease may be evident upon ocular examination and has also been reported in the lungs, liver, and bones.^{[5, 16]}

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Laboratory Studies

Pyoderma gangrenosum is a diagnosis of exclusion, in that no specific criteria have been established for confirming the diagnosis. All other potential causes of similar lesions must be excluded before the diagnosis of pyoderma gangrenosum is made.

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 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 (ANCA) test, a partial thromboplastin time (PTT) test, and an antiphospholipid antibody (APLA) test, all of which can help to rule out granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), vasculitis, and antiphospholipid syndrome.

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

Serum immunofixation electrophoresis is helpful for determining whether a monoclonal gammopathy is present. If it is present, it is most frequently an IgA subtype. Myeloma, however, is a rare association.

Tissue cultures of the ulcer or 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.

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Imaging Studies

Chest radiography may be performed. Angiography or Doppler ultrasonography (US) may be performed in patients suspected of having arterial or venous insufficiency.

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Other Tests

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

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Histologic Findings

The histopathologic findings in pyoderma gangrenosum are not specific. Nevertheless, a biopsy is suggested in almost all instances because it is useful for excluding other diseases (eg, infections and malignancy). Microscopic features of pyoderma gangrenosum include massive neutrophilic infiltration, hemorrhage, and necrosis of the overlying epidermis. Histologically, this finding may simulate an abscess or cellulitis, though no organisms are seen and cultures generally are negative or demonstrate only typical skin flora. Neutrophils are often around and within the vessel walls, but the full picture of vasculitis is usually 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. Therapy for pyoderma gangrenosum involves the use of anti-inflammatory agents, including antibiotics, corticosteroids, immunosuppressive agents, and biologic agents. Although surgical management should generally be avoided if possible, it is sometimes warranted. 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.

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

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

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Medical Care

Topical therapies include gentle local wound care and dressings, superpotent topical corticosteroids,^[19]  cromolyn sodium 2% solution, nitrogen mustard, and 5-aminosalicylic acid (5-ASA). The topical immune modifiers tacrolimus and pimecrolimus may have some benefit in certain patients.^[20]  A systematic review suggested that corticosteroid powder (from capsules or crushed tablets) could be a useful topical treatment in cases of peristomal pyoderma gangrenosum, in that it (unlike lotions or ointments) does not reduce pouch adhesion; however, further study would be needed to confirm this.^[21]

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

Intravenous (IV) therapies include pulsed methylprednisolone, pulsed cyclophosphamide, infliximab,^{[30, 31, 32, 33]} IV immunoglobulin (IVIG),^{[34, 35]} and ustekinumab.^[36]

Other therapies include hyperbaric oxygen (HBO).^[37]

Often, a corticosteroid (eg, prednisone) is prescribed initially. An immunosuppressive agent is also sometimes initiated, either simultaneously or subsequently; this is particularly the case in patients for whom high-dose long-term therapy is anticipated. Some physicians select cyclosporine as the initial therapy; azathioprine, mycophenolate, cyclophosphamide, chlorambucil, and tacrolimus have also been used.

The TNF-α inhibitors are close to being first-line agents in the treatment of pyoderma gangrenosum.

The interleukin (IL)-1β inhibitor canakinumab proved effective in a patient with pyoderma gangrenosum and concomitant hidradenitis suppurativa.^[38]

Biologic agents that are being studied for potential use in the treatment of pyoderma gangrenosum or other inflammatory conditions include IL-23 inhibitors^[39] (eg, risankizumab^{[40, 41, 42]} and guselkumab^[43] ), phosphodiesterase 4 (PDE4) inhibitors,^[44]  and Janus kinase (JAK) inhibitors,^{[45, 46]} as well as IVIG.^{[34, 47]}  

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Surgical Care

Surgery should be avoided if possible because of the pathergic phenomenon that may occur with surgical manipulation or grafting, resulting in wound enlargement.^[48]  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 where surgery or superficial debridement is required, the best plan, if feasible, is to have the patient on therapy, and active disease under control, in order to prevent the development of new pyoderma gangrenosum lesions.^[49]

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

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Consultations

Working with the primary care physician is wise for all patients. Depending on patient findings, however, it may be advisable to consult other specialists, such as the following:

• Gastroenterologist, colon and rectal 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; again, this should be performed with caution or while the patient is on appropriate therapy so as to prevent potential pathergy

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Long-Term Monitoring

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.

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Prednisone (Deltasone, Prednisone Intensol, Rayos)

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Methylprednisolone (A-Methapred, DepoMedrol, Medrol)

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Cyclosporine (Gengraf, Neoral, Sandimmune)

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Azathioprine (Azasan, Imuran)

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Mycophenolate (CellCept, MMF, Myfortic)

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Chlorambucil (Leukeran)

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Cyclophosphamide (Cytoxan)

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Thalidomide (Thalomid)

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Mechlorethamine (Nitrogen Mustard, Mechlorethamine hcl, Mustargen)

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Etanercept (Enbrel, Erelzi, Etanercept-szzs)

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Adalimumab (Abrilada, Adalimumab-aacf, Adalimumab-adaz)

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Certolizumab pegol (Cimzia)

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Golimumab (Simponi, Simponi Aria)

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Infliximab (Avsola, Inflectra, Infliximab-abda)

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Ustekinumab (Ustekinumab-aauz, Imuldosa, Otulfi)

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Risankizumab (Risankizumab-rzaa, Skyrizi)

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Guselkumab (Tremfya)

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Clofazimine (Lamprene)

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Immune globulin IV (IGIV) (Alyglo, Asceniv, Bivigam)

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Tacrolimus ointment (Protopic)

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Pimecrolimus (Elidel)

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Dapsone

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