AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Pyoderma gangrenosum (PG) is an uncommon ulcerative cutaneous condition of uncertain etiology. PG was first described in 1930. It is associated with systemic diseases in at least 50% of patients who are affected. The diagnosis is made by excluding other causes of similar appearing cutaneous ulcerations, including infection, malignancy, vasculitis, collagen vascular diseases, diabetes, and trauma. Ulcerations of PG may occur after trauma or injury to the skin in 30% of patients; this process is termed pathergy.

The 2 primary variants of PG are the classic ulcerative form, usually observed on the legs, and a more superficial variant known as atypical PG that tends to occur on the hands. Patients with PG may have involvement of other organ systems that manifests as sterile neutrophilic abscesses. Culture-negative pulmonary infiltrates are the most common extracutaneous manifestation. Other organs systems that may be involved include the heart, the central nervous system, the GI tract, the eyes, the liver, the spleen, bones, and lymph nodes. The prognosis of PG is generally good; however, recurrences may occur and residual scarring is common. Therapy of PG involves the use of anti-inflammatory agents, such as corticosteroids, and immunosuppressive agents.

Pathophysiology

The pathophysiology of PG is poorly understood, but dysregulation of the immune system, specifically altered neutrophil chemotaxis, is believed to be involved.

Frequency

United States

PG occurs in about 1 person per 100,000 people each year.

Mortality/Morbidity

Death from PG is rare, but it may occur due to an associated disease or as the result of therapy. Pain is a usual complaint of patients and may require narcotics. Pathergy, or the development of PG-like lesions at the site of skin trauma, may create problems with wound healing, especially after surgical procedures.

Race

No racial predilection is apparent.

Sex

PG affects both sexes. A slight female predominance may exist.

Age

All ages may be affected, but PG predominantly occurs in the fourth and fifth decades of life. Children may be affected, but they account for only 3-4% of the total number of cases. PG may affect children and adolescents. Nothing is clinically distinctive about these patients other than their age.

CLINICAL

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History

• Patients with PG usually describe the initial lesion as a bite reaction, with a small, red papule or pustule changing into a larger ulcerative lesion. 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 may often be present.
• A complete history should be taken with special focus on the organ systems listed below to determine any underlying systemic disease. Systemic illnesses are seen in 50% of patients with PG and may occur prior to, concurrently or following the diagnosis.
• • Commonly associated diseases include inflammatory bowel disease, either ulcerative colitis or regional enteritis/Crohn disease, and a polyarthritis that is usually symmetric and may be either seronegative or seropositive; and hematologic diseases/disorders, such as leukemia or preleukemic states, predominantly myelocytic in nature or monoclonal gammopathies (primarily immunoglobulin A [IgA]).
  • Less common associated diseases include other forms of arthritis, such as psoriatic arthritis, osteoarthritis, or spondyloarthropathy; hepatic diseases, including hepatitis and primary biliary cirrhosis; myelomas (IgA type predominantly); and immunologic diseases, such as lupus erythematosus and Sjögren syndrome.

Physical

• Two main variants of PG exist: classic and atypical. Several other variants may exist.
• • Classic PG is characterized by a deep ulceration with a violaceous border that overhangs the ulcer bed. These lesions of PG most commonly occur on the legs, but they may occur anywhere on the body (see Image 1).
  • Atypical PG has a vesiculopustular "juicy" component. This is usually only at the border, is erosive or superficially ulcerated, and most often occurs on the dorsal surface of the hands, the extensor parts of the forearms, or the face (see Image 2).
  • Classic PG may occur around stoma sites; this type is known as peristomal PG. This form is often mistaken for a wound infection or irritation from the appliance (see Image 3).
  • PG may occur on the genitalia; this form is termed vulvar or penile PG. This variant must be differentiated from sexually transmitted diseases.
  • An intraoral form of the disease, known as pyostomatitis vegetans, has been reported and occurs primarily in patients with inflammatory bowel disease.
  • Extracutaneous neutrophilic disease may be evident upon ocular examination and has also been reported in the lungs, liver, and bones.

Causes

No specific causes of PG have been identified, but trauma to the skin in patients with PG may induce new lesions. This is called pathergy.

DIFFERENTIALS

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Other Problems to be Considered

Antiphospholipid antibody syndrome
Anthrax
Arterial insufficiency
Acute febrile neutrophilic dermatosis (Sweet syndrome)
Blastomycosis
Factitial disease
Traumatic ulceration
Tuberculosis gumma

WORKUP

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Lab Studies

• Routine blood work to evaluate for an underlying systemic illness includes a CBC count; a comprehensive chemistry profile, including a liver function test; and a urinalysis.
• A hepatitis profile should be performed to rule out hepatitis.
• Serum and/or urine protein electrophoresis, peripheral smear, and bone marrow aspiration should be performed if indicated to evaluate for hematologic malignancies.
• Other serum studies include a Venereal Disease Research Laboratory (VDRL) test, antineutrophil cytoplasmic antibody test, partial thromboplastin time test, and antiphospholipid antibody test to rule out Wegener granulomatosis, vasculitis, and antiphospholipid antibody syndrome. Serum protein electrophoresis is helpful to determine if a monoclonal gammopathy is present. If present, it is often of the IgA subtype.
• 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.
• 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 PG and no symptoms of bowel disease is still uncertain.
• Angiography or Doppler studies may be performed in patients suspected of having arterial or venous insufficiency.

Other Tests

• The following tests may be performed:
• • Flexible sigmoidoscopy or colonoscopy in selected patients
  • Bone marrow aspiration or biopsy in selected patients
  • Culture of the ulceration and possibly of the biopsy material

Procedures

• A skin biopsy should be performed.

Histologic Findings

The histopathologic findings in PG are not specific. However, a biopsy is suggested in almost all instances because it is useful in the exclusion of other diseases. Microscopic features include massive neutrophilic infiltration, hemorrhage, and necrosis of the overlying epidermis. Histologically, this finding may simulate an abscess or cellulitis. 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 PG.

TREATMENT

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Medical Care

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

• Topical therapies include local wound care and dressings, superpotent topical corticosteroids, cromolyn sodium 2% solution, nitrogen mustard, and 5-aminosalicylic acid. The new topical immune modifiers tacrolimus and pimecrolimus may have some benefit in certain patients.
• Systemic therapies include corticosteroids, cyclosporine, mycophenolate mofetil, azathioprine, dapsone, tacrolimus, cyclophosphamide, chlorambucil, thalidomide, tumor necrosis factor-alpha (TNF-alpha) inhibitors, and nicotine.
• Intravenous therapies include pulsed methylprednisolone, pulsed cyclophosphamide, infliximab, and intravenous immune globulin.
• Other therapy includes hyperbaric oxygen.

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. In some patients, grafting has resulted in the development of PG at the harvest site. In the cases in which surgery is required, the best plan, if possible, is to have the patient on therapy in order to prevent pathergy.
• Some patients with ulcerative colitis have responded to total colectomy; however, in others, the disease is peristomal and occurs following bowel resection.

Consultations

• Depending on the findings in the patient, other specialists may be consulted. Working with the primary care physician is wise for all patients.
• • Gastroenterologist or GI surgeon, proctorectal surgeon, or general surgeon in 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

Diet

No special dietary needs are required.

Activity

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

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Glucocorticoids

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.

Drug Category: Immunosuppressives

These agents have immunomodulatory effects.

Drug Name	Azathioprine (Imuran)
Description	Another drug that may be effective as a steroid-sparing agent. Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
Adult Dose	1-2 mg/kg/d (50-200 mg) PO
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; low levels of serum TPMT; history of treatment with alkylating agents
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine; live virus vaccines may have a greater systemic effect; coadministration with other immunosuppressive agents may increase bone marrow suppression; increases in uric acid levels reported when administered concomitantly with tacrolimus
Pregnancy	D - Unsafe in pregnancy
Precautions	Reduce dose in patients with low TMPT levels; bone marrow suppression may occur; nausea and vomiting are commonly noted; may increase risk of lymphoproliferative disorders in patients treated with long-term therapy; cancer, hepatotoxicity, infectious disease, leukopenia, megaloblastic anemia, pancreatitis, and thrombocytopenia may occur

Drug Name	Mycophenolate (CellCept)
Description	Inhibits purine synthesis and proliferation of human lymphocytes. May be used as steroid-sparing agent or as primary agent in patients that do not respond to first-line agents.
Adult Dose	1-2 g/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May elevate acyclovir and ganciclovir levels; antacids and cholestyramine decreases absorption, reducing levels (do not administer together); probenecid may increase levels; salicylates may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Risk of lymphoma may increase in patients on long-term therapy; slightly higher rate of viral and bacterial infections is present while on therapy; GI disturbance and dose-related hematologic effects, including leukopenia, may occur; CellCept brand of oral susp contains aspartame, which is metabolized to phenylalanine (care should be taken if administered to patients with phenylketonuria)

Drug Name	Cyclophosphamide (Cytoxan)
Description	Alkylating agent that depresses B-cell and T-cell function. 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 growth of normal and neoplastic cells.
Adult Dose	1-2 mg/kg/d PO
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function; pregnancy
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life of cyclophosphamide while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	GI upset and oral stomatitis may occur in up to 70% of patients; hemorrhagic cystitis possible, particularly if drug is given without hydration; azoospermia or anovulation may occur after prolonged therapy; alopecia and hyperpigmentation of nails and skin may occur; perform routine CBC counts and urinalysis; cardiomyopathy, infectious disease, interstitial pneumonia, Stevens-Johnson syndrome, and toxic epidermal necrolysis may occur; possibility of increased toxicity in adrenalectomized patients; be aware of possibility of cross-sensitivity with other alkylating agents Patients with moderate renal failure (glomerular filtration rate [GFR] 10-50 mL/min) should receive 75% of normal dose given at usual dosage interval and patients with severe renal failure (GFR <10 mL/min) receive 50% of normal dose given at usual dosage interval (no dosage reduction required for mild renal failure (GFR >50 mL/min), although dosing interval should be increased to q12h; dosage may also be adjusted by increasing dosing interval as follows: GFR >10 mL/min, increase interval to >12 h; GFR <10 mL/min, increase interval to q18-24h; data show that patients with hepatic failure develop more toxicity with cyclophosphamide as opposed to patients with normal hepatic function

Drug Name	Chlorambucil (Leukeran)
Description	Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription. Used as primary or steroid-sparing agent.
Adult Dose	4-6 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; previous resistance to this medication; pregnancy
Interactions	Additive effect with other immunosuppressive agents
Pregnancy	D - Unsafe in pregnancy
Precautions	Decreases immune response to live viral vaccines; lymphopenia and neutropenia may occur (monitor CBC counts regularly); metabolism is decreased in patients with impaired hepatic function; hepatotoxicity; infertility, leukemia, myelosuppression, pancytopenia, peripheral neuropathy, pneumonitis, and secondary malignant neoplastic disease may occur; avoid administration of live vaccines to immunocompromised persons; do not administer full dosage within 4 wk of completion of full course of radiation therapy or chemotherapy (risk of bone marrow damage)

Drug Name	Tacrolimus (Prograf)
Description	Suppresses humoral immunity (T-lymphocyte) activity.
Adult Dose	0.05 mg/kg/d IV or 0.15-0.30 mg/kg/d PO divided bid
Pediatric Dose	0.1 mg/kg/d IV or 0.3 mg/kg/d PO
Contraindications	Documented hypersensitivity; hypersensitivity to tacrolimus products or hydrogenated castor oil (if IV formulation used)
Interactions	Diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, and clarithromycin may increase levels; coadministration of rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine may reduce levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not administer simultaneously with cyclosporine (tonic clonic seizures may occur); cardiomegaly, diabetes mellitus, hyperglycemia, hyperkalemia, hypertension, hypomagnesemia, prolonged QT interval, and malignant lymphoma may occur

Drug Category: Blood products

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.

Drug Category: Immunomodulators

These agents have effects on the activity of the immune system.

Drug Name	Etanercept (Enbrel)
Description	Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, thereby, decreasing inflammatory and immune responses.
Adult Dose	50-100 mg SC qwk
Pediatric Dose	0.4 mg/kg SC qwk
Contraindications	Documented hypersensitivity, sepsis, concurrent live vaccination, active granulomatous infection, heart failure, patients with demyelinating diseases
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Serious infections may develop and therapy should be discontinued if they occur; possible adverse effects include injection site pain, redness and swelling at injection site, and headaches; rare cases of lupuslike symptoms and heart failure reported (discontinue treatment if symptoms develop)

Drug Name	Infliximab (Remicade)
Description	Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas
Adult Dose	3-5 mg/kg IV infusion over 2-4 h Initial induction dose then repeat at week 2, then week 6, then q6-8wk May increase to 10 mg/kg IV q8wk for patients who respond, then lose their response; discontinue treatment in those who do not response by week 14
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity, congestive heart failure, active granulomatous disease, patients with history of tuberculosis or positive PPD test and are untreated, sepsis
Interactions	Crohn disease patients (adolescent and young adult) on concomitant treatment with azathioprine or 6-mercaptopurine have developed fatal hepatosplenic T-cell lymphomas; concomitant immunosuppressive therapy (risk of serious infection, including sepsis and pneumonia [some fatal cases]); concomitant use of infliximab and anakinra not recommended (increased risk for serious infection)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	TNF-alpha modulates cellular immune responses; anti-TNF therapies (eg, infliximab) may adversely affect normal immune responses and allow development of superinfections; more cases of lymphoma were observed in TNF-alpha blockers compared with control groups; may increase risk of reactivation of tuberculosis in patients with particular granulomatous infections; has been associated with lupus erythematosus; acute coronary syndrome, congestive heart failure, demyelinating disease of CNS or seizure disorder, hepatotoxicity, leukopenia, neutropenia, thrombocytopenia, and pancytopenia may occur; serum sickness?like reactions may occur upon reinstitution of infliximab therapy after extended period without therapy

Drug Name	Adalimumab (Humira)
Description	TNF-alpha inhibitor. Fully human inhibitor of TNF-alpha administered by SC injection.
Adult Dose	40 mg SC qwk or every other wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; rheumatoid arthritis, ulcerative colitis, psoriatic arthritis
Interactions	Concomitant use of adalimumab and anakinra not recommended (serious infections have occurred with concomitant use); risk for severe infection with concurrent immunosuppressive therapy (live vaccines should not be given concurrently)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Aplastic anemia, cancer, demyelinating disease of CNS, erythrocytosis, formation of autoantibodies; systemic lupus?like syndrome, infectious disease, leukopenia, malignant lymphoma, pancytopenia, tuberculosis recurrence, paresthesia, and subdural hematoma may occur

Drug Name	Clofazimine (Lamprene)
Description	Inhibits mycobacterial growth, binds preferentially to mycobacterial DNA. Has antimicrobial properties, but mechanism of action is unknown.
Adult Dose	200-400 mg/d PO qd
Pediatric Dose	1 mg/kg/d PO qd
Contraindications	Documented hypersensitivity
Interactions	Dapsone may inhibit anti-inflammatory activity; coadministration with antacids can result in reduced clofazimine bioavailability; may increase phenytoin clearance
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Severe abdominal symptoms may require exploratory laparotomies; caution in patients with GI problems (eg, abdominal pain, diarrhea); skin discoloration due to drug may result in depression or suicide; apply oil to skin for dryness and ichthyosis

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

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

In/Out Patient Meds

• Therapy with corticosteroids is often prescribed initially. Sometimes, an immunosuppressive agent is also initiated later or simultaneously, particularly in those patients for whom high-dose long-term therapy is anticipated. Some physicians select cyclosporine as the initial therapy. The TNF inhibitors are showing promise in the treatment of PG.

Transfer

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

Prognosis

• The prognosis of PG is generally good; however, recurrences may occur, and residual scarring is common.
• Many patients with PG improve with initial immunosuppressive therapy and require minimal care afterwards; however, many patients follow a refractory course and multiple therapies fail. These patients pose a difficult clinical problem that requires frequent follow-up and long-term care.
• Some patients demonstrate pathergy, and, in such instances, protection of the skin from trauma may prevent a recurrence.

MISCELLANEOUS

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Medical/Legal Pitfalls

• PG is often misdiagnosed and multiple attempts at grafting often occur prior to the diagnosis being made. The breakdown at the harvest site is a clue to the diagnosis and is an indicator of pathergy often seen in active PG patients.
• PG is a diagnosis of exclusion because 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.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Classic or typical pyoderma gangrenosum. This patient did not have an associated disease, and the condition responded well to cyclosporine.
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Media file 2:  Atypical pyoderma gangrenosum.
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Media file 3:  Peristomal pyoderma gangrenosum.
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REFERENCES

Section 11 of 11

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• Koester G, Tarnower A, Levisohn D, Burgdorf W. Bullous pyoderma gangrenosum. J Am Acad Dermatol. Nov 1993;29(5 Pt 2):875-8. [Medline].
• Matis WL, Ellis CN, Griffiths CE, Lazarus GS. Treatment of pyoderma gangrenosum with cyclosporine. Arch Dermatol. Aug 1992;128(8):1060-4. [Medline].
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Article Last Updated: Sep 12, 2006