Chapter 33. Pyoderma Gangrenosum

The prevalence of pyoderma gangrenosum (PG) is unknown. Estimates have suggested that approximately three cases of PG per million of the population occur per year, with most large referral centers seeing one to two cases per year.1 It has been reported in all age groups but mainly affects adults between the ages of 40 and 60 years.2 Most reported series of patients with PG indicate a moderate preponderance of females. PG often occurs in patients who have other diseases (arthritis, inflammatory bowel disease, hematologic dyscrasias, etc.), but is not a manifestation or complication of these diseases and its clinical course is usually unrelated to their severity or activity.3

The etiology of PG is unknown, and its pathogenesis poorly understood. Based on the presence of a lymphocytic infiltrate at the active advancing border of PG lesions, it has been postulated that lymphocytic antigen activation occurs with cytokine release and neutrophil recruitment. This may take place not only in the skin but also in other tissues such as the lung, intestine, and joints. The predominance of the neutrophilic infiltrate in established lesions of PG have led to its classification as one of the neutrophilic dermatoses.4 Clinical (and to an extent histologic) overlap occurs with the other dermatoses in this category, especially atypical or bullous forms of Sweet syndrome (see Chapter 32). Several of the neutrophilic dermatoses (Sweet syndrome, erythema elevatum diutinum, subcorneal pustular dermatosis, and PG) share an association with immunoglobulin A monoclonal gammopathy, and diseases such as inflammatory bowel disease and hematologic disorders occur more frequently than expected in these patients. The recent description of the PAPA (Pyogenic Arthritis, Pyoderma gangrenosum-Acne) syndrome,5 a disease considered to be one of the “autoinflammatory” diseases, raises the possibility that PG may lie within this spectrum.

The approach to an individual suspected of having PG is outlined in the patient algorithm (Fig. 33-1). The clinical presentation of PG may be diverse and there is neither a diagnostic laboratory test nor pathognomonic histopathologic findings. Therefore, it is important to avoid misdiagnosing other diseases as PG.6 The most important considerations are the exclusion of infection (bacterial, viral, and deep fungal), vascular disease (stasis, occlusion, and vasculitis), and malignancy in every patient. Close follow-up and reevaluation (with repeated skin biopsies, tissue and swab cultures, and other tests as clinically indicated) is an important part of the ongoing evaluation of patients with suspected PG, particularly those who show a poor response to therapy.

History

A patient with PG usually complains of severe pain that is out of proportion to the clinical appearance of the lesion. Approximately 25% of patients note the onset of PG at sites of cutaneous trauma (needle stick, inoculation site, insect bites, or surgical procedures). This is called the pathergic phenomenon (Fig. 33-2). Lesions progress rapidly (with the exception of vegetative PG) and cutaneous destruction evolves over days rather than weeks. Special inquiry regarding drug intake (especially iodides/bromides, hydroxyurea); exposure to and symptoms of infectious diseases (Box 33-1); symptoms relating to the musculoskeletal system (joint pains, swelling, etc.), the gastrointestinal tract (abdominal pain, diarrhea, constipation, etc.), hematologic disease (tiredness, anemia, bruising, blood clotting disorders, etc.), respiratory disease, and nonspecific but potential malignancy-related symptoms, such as weight loss and fatigue, should be made.

Cutaneous Lesions: Clinical Variants of PG

PG is protean in its clinical expression with variable presentation according to the variant and the stage of disease. Lesions can be classified morphologically as being (1) ulcerative (the commonest and originally described variant), (2) bullous, (3) pustular, or (4) vegetative. Although some patients may show more than one variant (e.g., isolated pustular lesions frequently occur in patients with ulcerative PG), usually one variant of PG dominates the clinical picture and the patient should be classified accordingly.

The most common initial clinical lesion in a patient with ulcerative PG is an inflammatory pustule or nodular furuncle (these lesions are usually single but may be multiple). They erupt on apparently normal skin (the most common site being the leg), or sometimes at the site of trauma or surgery (Fig. 33-2). The enlarging initial lesion develops a surrounding areola or zone of erythema that extends into the surrounding skin (Fig. 33-3). As it enlarges, the center degenerates, crusts, and erodes, converting it into an eroding ulcer the development of which is accompanied by an alarming increase in the severity of the pain. The ulcer often has a bluish/violaceous edge (due to undermining by the necrotizing inflammatory process) and the base is covered with purulent material. Ulcerative PG may erode deeply with exposure of muscle or tendon in some cases.

Bullous PG (sometimes called atypical PG) presents as a painful, rapidly expanding superficial inflammatory blister that quickly erodes. In the early acute stage, the bullous nature of the lesion is evident, but because the roof of the blister necroses rapidly, close inspection of the border of established lesions is necessary to reveal its bullous nature (Fig. 33-4). Bullous PG is commonly associated with hematologic disease and most often appears on the upper limbs.2 This variant of PG may show clinical and histological overlap with Sweet Syndrome (one of the neutrophilic dermatoses which is itself often associated with hematologic disease).

Pustular PG (also called the pustular eruption of inflammatory bowel disease) is a generalized eruption that occurs almost exclusively in the setting of an exacerbation of acute inflammatory bowel disease (usually ulcerative colitis). Its onset is dramatic, with the rapid development of multiple, large, circular-to-oval, painful pustules on the trunk and, to a lesser extent, the face and limbs (Fig. 33-5). Control of this eruption is difficult without controlling the bowel disease, which in some cases requires extensive resective surgery.

Vegetative PG (or superficial granulomatous pyoderma) usually presents as a single furunculoid nodule, abscess, plaque, or superficial ulcer, typically on the trunk (Fig. 33-6). In contrast to other variants, it is gradual in its onset, mild in the discomfort it generates, and not usually associated with the presence of systemic disease. This form of PG is usually more responsive to localized or mild forms of systemic therapy than the other variants.7

Postoperative and Peristomal PG are considered to be examples of ulcerative PG demonstrating the pathergic phenomenon, while the PAPA syndrome has recently been reported as an autosomal dominant condition classified as being one of the group of “autoinflammatory” diseases.

Related Physical Findings

The clinician should be aware that sterile neutrophilic abscesses of internal organs (lung, bone joints, CNS, CVS, intra-abdominal viscera, eye) can occur in association with or even precede the onset of cutaneous PG.7 In the patient without cutaneous lesions surgical procedures may be undertaken to establish the diagnosis of the internal neutrophilic infiltration, the wounds of which may subsequently break down and present as postoperative PG. Because many patients with PG also have diseases of other systems (more than 70% of cases), a thorough physical examination is mandatory with particular search for clinical and biological markers of inflammatory bowel disease, arthritis, vasculitis (leukocytoclastic/granulomatous/cryoglobulinemic/Takayasu arteritis), hematologic disease (monoclonal gammopathy and other dyscrasias), and internal malignancy.

Routine Investigations

(See Fig. 33-1)

All patients with PG should have the following tests carried out: full blood cell count with differential white cell count and erythrocyte sedimentation rate liver, and bone profiles; autoantibody screen (including anti-Ro/La antibodies, antineutrophilic cytoplasmic antibodies, antiphospholipid antibodies, rheumatoid factor); serum protein electrophoresis; thyroid function studies; chest X-ray (Fig. 33-7), electrocardiogram, and midstream specimen of urine; and swabs from lesions sent for bacterial, fungal, and viral cultures. An incisional, wedge skin biopsy should be taken from the edge of the lesion sampling a portion of normal skin progressing through the border into the area of active inflammation to allow the various histological patterns to be discerned. The excised tissue should then be divided with one section (fresh tissue) sent for bacterial, mycobacterial, and fungal culture, and another portion sent in formalin for histological evaluation requesting hematoxylin and eosin and periodic acid-Schiff, Giemsa, Fite, Gram, and other stains considered relevant. Although immunofluorescent studies may show positive vascular staining in perilesional skin, this is not essential for diagnostic purposes and can be omitted unless vasculitis is suspected in the differential diagnosis.

Histopathology

The histopathological changes in the skin are not diagnostic but can be highly suggestive of PG and require experience to interpret. The inflammatory changes that are seen depend on (1) the clinical variant of PG (ulcerative, bullous, pustular, or vegetative), (2) the timing of the biopsy (early lesions show less marked changes than established lesions), and (3) the site of the biopsy relative to the inflammatory process.8 The site of the biopsy is particularly important because biopsies taken from the center of established ulcerative, bullous, or pustular PG lesions usually show marked neutrophilic infiltration with abscess formation in the mid and deep dermis extending to the panniculus, whereas those taken from peripheral areas (the ulcer edge or inflammatory zone of erythema) show a mixed or predominantly lymphocytic inflammatory infiltrate.

A marked perivascular lymphocytic infiltration is seen in biopsies taken from the “zone” or area of erythema which surrounds active lesions of ulcerative PG. Lymphocytes may be seen to infiltrate vessel walls with intramural and intravascular fibrin deposition indicative of vascular damage (sometimes called lymphocytic vasculitis).9 Abscess formation with intense dermal neutrophilic infiltration extending to the panniculus and areas of tissue necrosis dominates the histological findings in biopsies taken from central areas of ulcerative PG lesions. Leukocytoclasis is not a prominent finding and although occasionally evidence of leukocytoclastic vasculitis is seen close to the abscess center, this is a minor feature and considered secondary to the intense inflammatory changes rather than the primary event. Histological examination of lesional skin from a patient with bullous PG shows a subepidermal or intraepidermal bulla with overlying epidermal necrosis and marked upper dermal edema with prominence of neutrophils. Biopsy of pustular PG shows a dense dermal neutrophilic infiltration (often centered about a follicle) with subepidermal edema and infiltration of neutrophils into the epidermis with subcorneal aggregations. Vegetative PG is characterized histologically by the presence of pseudoepitheliomatous hyperplasia, sinus tract formation, and the presence of palisading granulomas in the setting of focal dermal neutrophilic abscesses.

Special Investigations

In some patients the following additional tests may be warranted: endoscopy (upper and/or lower gastrointestinal); vascular studies; bone marrow aspirate examination; ultrasound of abdomen (including liver/spleen/aorta); computed tomography of the thorax, abdomen, or brain; and other directed investigations as outlined in Fig. 33-1.

The differential diagnosis to be considered in a patient with PG is extensive.6 Different variants of PG (ulcerative, bullous, vegetative, pustular) suggest alternative diagnoses and the occurrence of PG at certain cutaneous sites raises further diagnostic issues for the clinician, as shown in Box 33-1.

Because there is no confirmatory diagnostic test for PG, the following major criteria are proposed which make the diagnosis of PG likely:

1. Major criteria are as follows:

   1. Sudden onset of a painful lesion fitting the morphologic descriptions outlined above (ulcerative, bullous, pustular, or vegetative) in a (usually middle-aged) apyrexial patient without significant toxemia or relevant drug intake

   2. Histological evidence of marked tissue neutrophilia in the absence of significant leukocytoclastic vasculitis and histopathological exclusion of malignancy and of infective organisms by special studies and negative tissue culture

   4. Exclusion of vascular stasis/occlusion/vasculitis by appropriate studies

2. Minor criteria that are supportive of the diagnosis are as follows:

   1. Localization of lesions at characteristic sites (ulcerative PG on the legs, vegetative on the trunk, bullous PG on the upper limb, pustular PG on the trunk or face) or at a site of cutaneous trauma (postoperative ulcerative PG or peristomal PG).

   2. Rapid progression of the inflammatory lesion with escalating pain severity (except vegetative PG).

   4. Occurrence in an individual with systemic disease, such as arthritis, inflammatory bowel disease, or hematological dyscrasias (except vegetative PG).

   6. Rapid reduction of pain and inflammation on initiation of systemic steroid therapy.

Active or poorly controlled cutaneous PG causes significant morbidity (loss of mobility, pain, exposure to secondary infection, anemia of chronic disease, etc.). Lack of recognition of the neutrophilic infiltration of internal organs in PG may lead to unnecessary surgical procedures. Many of the treatments for PG must be administered for many months and may have significant side effects. Frequent monitoring and follow-up of patients are necessary. Elective surgery should be undertaken with caution because of the possibility of inducing new PG lesions.

The prognosis depends on the PG variant; the age and sex of the patient; presence of other systemic disease; and the type, dosage, and duration of therapy required to bring the disease under control. Patients with vegetative PG generally have a good prognosis and the skin lesions often heal within 6 months of the initiation of relatively mild forms of treatment.7 Peristomal PG similarly has a good prognosis often responding to topical or intralesional therapy. Patients with pustular PG often have complete remission of their cutaneous lesions if the severe inflammatory bowel disease that usually accompanies this variant is controlled. Ulcerative PG is a chronic recurrent disease with a significant morbidity and mortality.2,10 Patients with this variant older than 65 years of age and male patients seem to have a worse prognosis. Patients with bullous PG who have an associated hematological disorder also have a poor prognosis. The onset of bullous PG in a patient with stable polycythemia rubra vera appears to herald the onset of leukemic change in some patients.11

General Measures

The age, mobility, social support networks, pain threshold, extent and severity of disease, and ability to comply with therapeutic measures should be evaluated for each patient and the treatment adapted accordingly. The patient should be given realistic expectations of the speed of recovery likely in this disease. Thus, although lesions develop and evolve within days, the healing process usually takes weeks or even months. Adequate bed rest, efficient pain relief, correction of anemia, and appropriate therapy of any associated disease are pivotal in the overall management strategy of a patient with PG.12 If other systemic illnesses are present, cooperation with an internal medicine specialist is important, and if surgery is anticipated appropriate measures (such as the use of subcuticular sutures and systemic steroid cover) should be adopted to avoid precipitating new postoperative PG lesions.

The location, morphology, size, and outline of each lesion should be recorded (by photography and by using a calibrated transparent plastic sheet placed over lesions on which the outline is traced) on presentation and subsequent review.

Wound Care

The cutaneous lesions of PG are usually extremely tender so cleansing should be carried out daily with tepid sterile saline or a mild antiseptic solution. Potassium permanganate solution diluted 1:2,000 is helpful if there is marked exudation. Silver sulphadiazine 1% cream is usually soothing when applied to the ulcerated lesions of PG and may facilitate granulation tissue formation as well as inhibiting bacterial growth. A nonadhesive dressing should be applied over the lesion and held in place with a crêpe elasticized bandage wound firmly, but not tightly, over it. Some patients, particularly those with superficial lesions, obtain significant relief with the use of hydrocolloid dressings, which can be left on for 2–3 days and “melt” into the lesion. Careful instruction to the patient and nurse is important to ensure compliance and to avoid the use of irritants such as chemical desloughing agents, caustics (such as silver nitrate), or dressings (such as gauze impregnated with soft paraffin and/or antibacterial agents which may adhere to the ulcer base) or pressure dressings as are sometimes prescribed for patients with ulcers due to venous insufficiency. A variety of bacteria may be cultured from the wound surface, but these usually represent contaminants and directed antibiotic therapy is not required unless there are clinical signs of incipient cellulitis around the wound.

Topical Treatments

Topical treatments are important adjuncts to the systemic treatment needed for the management of most PG patients, and may be sufficient to bring the condition under control in those who have vegetative or mild ulcerative PG. Potent topical corticosteroids applied to the periphery of an active PG lesion can reduce inflammation and may be sufficient to heal vegetative or peristomal ulcerative PG.13 Although topical disodium cromoglycate (with or without occlusion), benzoyl peroxide, nicotine cream or patches, hyperbaric oxygen, and radiotherapy have all been reported as being helpful in individual patients with PG, their effectiveness has not been established. Clinical impression suggests that topical tacrolimus (with or without occlusion) is particularly effective for isolated pustular lesions and for the superficial ulcerations of peristomal PG.

Intralesional Treatments

Intralesional triamcinolone acetonide (5–10 mg/mL) injected twice weekly into the border of a vegetative or peristomal PG lesion may lead to healing and can also be useful in a patient with ulcerative PG if one section of the ulcer is proving recalcitrant to other therapies. Intralesional cyclosporine and tacrolimus have also been reported to be effective in some PG patients.

Systemic Treatments

Because PG is a rare disease, most systemic treatment recommendations are based on experience gained from small series of patients studied.14 The main systemic treatments used for PG with their suggested dosages are listed in Box 33-2. As experience with newer agents is gained, it is likely these recommendations will change.15 The initiation of systemic therapy is based on the variant of PG (ulcerative and bullous PG usually require systemic therapy), the rapidity of its evolution, the extent of cutaneous involvement, and the general medical status of the patient.

Systemic corticosteroid treatment is probably the initial treatment of choice for most patients with PG. It is important to initiate systemic steroids at a sufficiently high dose to control the disease. Rapid diminution of pain is often recorded by the patient after initiation of therapy and steroids should be continued at this dosage until lesions show evidence of healing, after which gradual tapering of the dose can be undertaken. A steroid-sparing agent should be added as soon as possible, as well as bone protective measures to diminish the risk of osteoporosis because prolonged therapy can be anticipated in most patients. Intravenous corticosteroids in pulsed doses have been used to induce PG remission, but serious potential adverse effects limit their use to exceptional circumstances. Dapsone has been traditionally used in the treatment of PG and remains a useful drug, particularly when used in conjunction with systemic corticosteroids. Dapsone is generally well tolerated, but hematological complications (including agranulocytosis, hemolysis, hemolytic anemia, and methemoglobulinemia) as well as other potentially serious side effects may occur. Other antimicrobial agents reported as successful in the treatment of PG patients include rifampicin, tetracyclines, vancomycin, mezlocillin, clofazimine, and minocycline. These have usually been prescribed in combination with other systemic therapies and seem to work in PG patients by mechanisms other than their antibacterial properties. Most experience has been with clofazimine and minocycline (100–200 mg daily). The latter agent is well tolerated and often allows for a reduction in systemic corticosteroid dosage and appears to prolong remission in some patients.

Cyclosporine is an alternative first-line therapy of PG16 or may be used in combination with systemic corticosteroids to achieve rapid control of disease. Doses of 3 to 5 mgs/kg/day have shown efficacy and continued treatment is usually required for 3–4 months. Less risk of serious side effects (such as impairment of renal function and hypertension) is seen at these low doses, but careful monitoring of patients is required and attention should paid to the possibility of other drugs interacting with this medication.

Tacrolimus (FK-506) and mycophenolate mofetil have also been used successfully in the treatment of PG either as monotherapies or in combination with systemic corticosteroids or cyclosporine.17 Both drugs cause significant immunosuppression with resultant susceptibility of the patient to infection and malignant disease and can have other potentially serious side effects. Infliximab, an antitumor necrosis factor antibody, has been used successfully to treat patients with inflammatory bowel disease and has been reported to be effective in some patients with PG.18 Other similar drugs that have been reported to be efficacious in the treatment of patients with PG include etanercept and adalimumab. The role of these agents in the management of PG has yet to be fully defined and susceptibility to reactivation of tuberculosis infection and other significant side effects remain a concern. Anakinra, an IL-1 receptor antagonist has been reported to be effective in treating PG of the PAPA syndrome and suggests another possible treatment for this condition.5 The use of thalidomide in the treatment of PG has probably been superseded by the development of these other agents. Other drugs which have been reported to be helpful in the treatment of PG include azathioprine (thiopurine methyl transferase levels should be checked pretreatment), colchicine,19 cyclophosphamide, chlorambucil, and melphalan. These agents can have toxic effects and evidence of their efficacy is limited.

Other modalities which have been reported to be useful in the management of individual patients or small series of patients with PG include human intravenous immunoglobulin,20 interferon-α, nicotine,21 potassium iodide, leukocytapheresis,22 and plasma exchange. Skin grafting should be avoided if possible because of the risk of inducing new PG lesions at the donor sites, but cultured tissue allografts/autografts and the use of bovine collagen matrix have been reported to be useful in patients in whom the disease is controlled but reepithelialization incomplete.23

The unpredictable nature of PG and its variable aggressiveness in individual patients mean that a flexible approach to treatment is required and the use of therapeutic agents have to be adapted to the patient's physiologic state (childhood, pregnancy, old age). By whichever modality control of PG is achieved, maintenance therapy should be continued until there is complete wound healing. In addition, patients with ulcerative PG have a significant risk of relapse, so long-term follow-up is required.

A patient who has had a history of PG should be advised to avoid trauma to the skin as there is the possibility of precipitating a new lesion (the pathergic phenomenon). If such patients have to undergo surgery, they should have close supervision by a dermatologist of their postoperative course. Patients with a history of aggressive PG may warrant a course of systemic steroids during and for a period (2 weeks or longer) postoperatively to prevent the development of new PG lesions and subcuticular sutures should be used where possible. Patients with a history of PG and Crohn's disease who are to have an ileostomy should be warned about the possible development of peristomal PG lesions.