Clinical Management of Pyoderma Gangrenosum

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THERAPY IN PRACTICE

Am J Clin Dermatol 2002; 3 (3): 1 1175-0561/02/0003-0001/$25.00/0 © Adis International Limited. All rights reserved.

Clinical Management of Pyoderma Gangrenosum Uwe Wollina Department of Dermatology, Hospital Dresden-Friedrichstadt, Dresden, Germany

Contents Abstract . . . . . . . . . . . . . . . 1. History . . . . . . . . . . . . . . . 2. Epidemiology . . . . . . . . . . . . . 3. Etiology and Pathogenesis . . . . . . 4. Clinical Presentations . . . . . . . . . 5. Histopathology . . . . . . . . . . . . 6. Laboratory Findings . . . . . . . . . . 7. Diagnosis and Differential Diagnosis 8. Associated Disease . . . . . . . . . . 9. Treatment . . . . . . . . . . . . . . . 9.1 Topical Therapy . . . . . . . . . 9.2 Systemic Therapy . . . . . . . . 9.3 Surgical Therapy . . . . . . . . . 10.Conclusion . . . . . . . . . . . . . . .

Abstract

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Pyoderma gangrenosum is a noninfectious neutrophilic dermatosis that usually starts with sterile pustules which rapidly progress to painful ulcers of variable depth and size with undermined violaceous borders. In 17 to 74% of cases, pyoderma gangrenosum is associated with an underlying disease, most commonly inflammatory bowel disease, rheumatologic or hematological disease or malignancy. Diagnosis of pyoderma gangrenosum is based on a history of an underlying disease, typical clinical presentation and histopathology, and exclusion of other diseases that would lead to a similar appearance. Randomized, double-blinded prospective multicenter trials investigating the treatment of pyoderma gangrenosum are not available. The treatments with the best clinical evidence are systemic corticosteroids (in the initial phase usually 100 to 200 mg/day) and cyclosporine (mainly as a maintenance treatment). Combinations of corticosteroids with cytotoxic drugs such as azathioprine, cyclophosphamide or chlorambucil are used in patients with disease that is resistant to corticosteroids. The combination of corticosteroids with sulfa drugs, such as dapsone, clofazimine, minocycline and thalidomide, has been used as a corticosteroid-sparing alternative. Limited experience has been documented with methotrexate, colchicine, nicotine, and mycophenolate mofetil, among other drugs. Alternative treatments include local application of granulocyte-macrophage colony-stimulating factor, intravenous immunoglobulins and plasmapheresis. Skin transplants (split-skin grafts or autologous keratinocyte grafts) and the application of bioengineered skin is useful in selected cases in conjunction with immunosuppression. Topical therapy with modern wound dressings is useful to minimize pain and the high risk of secondary infection. The application of topical antibacterials cannot be recommended because of their potential to sensitize and their questionable efficacy, but systemic antibacterial therapy is mandatory when infection is present. Despite recent advances in therapy, the prognosis of pyoderma gangrenosum remains unpredictable.

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1. History Brunsting et al.[1] were the first to describe pyoderma gangrenosum as an entity; however, as far back as the early 19th century, Marie-Nicolas Devergie was illustrating the disease in his atlas ‘Clinique de la Maladie Syphilique’ ((Author: does reference 2 relate to a review of the history of pyoderma gangrenosum?)).[2] In 1930, Brunsting et al.[1] reported a group of five patients with recurrent cutaneous ulcerations and mucopurulent or hemorrhagic exudate. These patients presented with ulcers with undermined bluish borders and surrounding erythema. The isolation of bacteria, in combination with the presence of an underlying disease (empyema in one, ulcerating colitis in four), suggested to the authors that the skin lesions developed as a consequence of the spread of infection in immunocompromised patients. Their hypothesis is still reflected by the name of the disease ‘pyoderma gangrenosum’.

Fig. 2. A patient with ecthyma-like pyoderma gangrenosum of the amputation

stump, triggered by the prosthesis.

3. Etiology and Pathogenesis 2. Epidemiology Exact epidemiologic data on pyoderma gangrenosum are missing ((Author: not available?)), but the disease is considered to be uncommon. The peak of its incidence occurs in patients between the ages of 20 to 50 years, with women more often affected than men.[3,4] Incidences of pyoderma gangrenosum in infants and adolescents account for only 4% of all cases. Graham et al.[5] reviewed 46 infants and children with pyoderma gangrenosum and found an underlying disease in 74% of cases. The disease has also occasionally been reported in elderly people.[6]

Fig. 1. A patient with pyoderma gangrenosum of the distal foot, showing the typical

undermined inflamed border pattern.

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Bacterial infection in an immunocompromised patient was the initial definition of pyoderma gangrenosum; however, it is no longer considered a primary infectious disease. Fulbright et al.[7] hypothesized that pyoderma gangrenosum results from an aberrant immune response to yet unidentified factors. Depositions of proteins in skin vessels in pyoderma gangrenosum lesions have suggested an Arthus-like reaction.[8] Since inflammatory bowel disease is the most common underlying disorder, cross-reacting antigens in the bowel and the skin could be responsible for secondary cutaneous manifestations.[4] In recent years, there has been much success in understanding neutrophil interactions with their microenvironment. Cellular analysis of pyoderma gangrenosum has demonstrated aberrant integrin oscillations on neutrophils and aberrant neutrophil tracking of patients with the disease.[9,10] Elafin, an elastase inhibitor released by keratinocytes, was found in higher than normal levels in subcorneal layers of skin in patients with pyoderma gangrenosum. Neutrophil derived cytokines, such as interleukin1 and tumor necrosis factor-α, seem to be involved in the overexpression of elafin.[11] This pathway, thought to protect the epidermis from neutrophil infiltration, seems to not be adequate in patients with pyoderma gangrenosum, resulting in tissue necrosis. Genetic background seems to be related to mesoderm development (MESD) candidate genes. Microsatellite instability of the human bacterial artificial chromosone/yeast artifical chromosome physical map on chromosome 15 (corresponding to functional regions on mouse chromosome 7) like MESD, cosegregate Am J Clin Dermatol 2002; 3 (3)

Pyoderma Gangrenosum

with PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome.[12]

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Table I. Classification of pyoderma gangrenosum[18] Clinical variant of pyoderma gangrenosum Ulcerative

4. Clinical Presentations Pyoderma gangrenosum occurs most commonly on the lower legs, mainly in the pretibial area((Author: please provide a reference)). This may reflect the tendency of the disease to occur at sites of trauma((Author: please provide a reference)). However, spontaneous ulcerations without any notable trauma are not uncommon((Author: please provide a reference)). There are reports of pyoderma gangrenosum on other sites of the body, including breast, hand, trunk, head and neck, and peristomal skin; in severe cases pyoderma gangrenosum seems to effect the upper airway mucosa as well((Author: please provide a reference)). In patients with pyostomatitis, a differential diagnosis of underlying bowel disorders can be difficult.[13,14] Sterile pulmonary neutrophilic infiltrates[15] and neutrophilic myositis[16] have been reported in pyoderma gangrenosum as another extracutaneous manifestation of the disease. The ulcer starts as a follicular pustule with rapid growth, tissue necrosis and enlargement of the area. In the early stages the appearance is ecthyma-like; bullous pyoderma gangrenosum has been observed((Author: please provide a reference)). During surgery, traumatization itself can induce the ulcerations. The surrounding skin is erythematous with infiltration and edema; the ulcer borders are typically undermined and violaceous or bluish (figure 1 and figure 2). The ulcers develop a purulent cover, which rapidly becomes malodorous due to secondary infection. The depth of ulcers may vary markedly. Patients with flat and small ulcers have a better prognosis than patients with large ulcers that involve the deep subcutaneous tissues, including tendons and muscles (figure 3)((Author: please provide a reference)). Pain is a hallmark of the disease, it is a major symptom ((Author:

Pustular

Bullous

Vegetative

Typical course Ulceration with rapidly evolving purulent wound ground, aggressive immunosuppressive treatment necessary to control disease Discrete pustules, sometimes self-limited; commonly associated with inflammatory bowel disease Superficial bullae with development of ulcerations, systemic immunosuppression necessary Erosions and superficial ulcers, good response to less aggressive treatments

are there other major symptoms?))responsible for morbidity and loss of quality of life.[4,14,17] Powell et al.[18] suggested a classification of pyoderma gangrenosum into four major clinical types (table I). 5. Histopathology The histopathology of pyoderma gangrenosum is not specific. It changes with the stage of lesion and depends on where the biopsy was taken. The initial lesions show a deep suppurative folliculitis with a dense neutrophilic infiltrate. In the center of an ulcer, purulent dermatitis and panniculitis, with numerous macrophages and multinucleated histocytes, occur. Within the violaceous border, epidermal hyperplasia with acanthosis and spongiosis is noticeable. In spreading lesions, intraepidermal microabscesses filled with neutrophils and an intense papillary edema can be found. In the surrounding skin, a mixed infiltrate with a predominance of lymphocytes, and vascular changes, like endothelial swelling and angioplasia, may be prominent. With regressive lesions, plasma cells and macrophages invade the dermis and eventually fibrosis replaces inflammation. About 40% of patients have leukocytoclastic vasculiPyoderma gangrenosum with (necrotizing) tis.[8,19] granulomatous inflammation has been described in the literature.[20,21] These reports illustrate the difficulties of a diagnosis based solely on histopathology, since concomitant occurrence of pyoderma gangrenosum and systemic necrotizing vasculitis have been observed. 6. Laboratory Findings

Fig. 3. ’Malignant’ pyoderma gangrenosum. Extensive deep ulcers in an 18-yearold man.


There is no specific laboratory finding for pyoderma gangrenosum. In those patients with an underlying disease, laboratory parameters may reflect activity of those disorders. In Am J Clin Dermatol 2002; 3 (3)

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Table II. Diseases associated with pyoderma gangrenosum More frequent associations Inflammatory bowel disease, including: Colitis ulcerosa ((Author: Ulcerative colitis?)) Crohn’s disease Diverticulitis Myeloproliferative disease, including: Aplastic anemia

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those with sui generis pyoderma gangrenosum, the activity of inflammation may be reflected by blood sedimentation rate, Creactive protein ((Author: levels))and protein electrophoresis. Laboratory investigations, however, may be helpful in distinguishing pyoderma gangrenosum from other ulcerating disorders, such as anticardiolipin syndrome, other autoimmune connective tissue diseases, and true pyoderma or other infectious diseases, such as syphilis, etc.[3,4,6,14,17]

Essential thrombocytopenia Hodgkin’s disease Leukemia (different types) Monoclonal gammopathy Myelofibrosis Myeloma Non-Hodgkin’s lymphoma Polycythemia vera Rheumatologic disease, including: Osteoarthritis Psoriatic arthritis Relapsing polychondritis Rheumatoid arthritis Seronegative arthritis Spondylitis (different types) Sterile chronic multifocal osteomyelitis Systemic lupus erythematosus Takayasu syndrome Less frequent associations (incomplete list) Acne conglobata Chronic active hepatitis Complement deficiency Diabetes mellitus Erythema elevatum diutinum Fanconi’s anemia Hemoglobinemia Hepatitis C Hidradenitis suppurativa

7. Diagnosis and Differential Diagnosis The diagnosis of pyoderma gangrenosum is primarily a clinical one, supported by biopsy for histopathology. A patient’s history of possible underlying disease, and specific investigations based on that background, are necessary. Regular swabs from the ulcer ground should be taken to monitor the presence of secondary infection. The spectrum of differential diagnoses is broad. Early lesions can be mistaken for folliculitis, furunculosis, insect bites and ecthyma. Ulcers due to deep mycoses, tuberculosis, syphilis, leishmaniasis, herpes necroticans, adverse effects of drugs (heparin-associated necrosis, anticancer drugs, intravenous drug abuse, etc.), and tropical disease like blastomycosis or buruli ulcer, should also be considered. Patients with rheumatic and autoimmune connective tissue disease, including rheumatoid arthritis, systemic lupus erythematosus, Behcet’s disease or scleroderma, may develop ulcerating skin lesions. Localized pemphigus or pemphigoid have to be differentiated from pyoderma gangrenosum and its bullous variant. Malignant ulcers can resemble pyoderma gangrenosum. Sweet’s syndrome shows some clinical and histopathologic overlap with pyoderma gangrenosum; it can develop together with pyoderma gangrenosum, or change from one to the other in the same patient.[19,22,23] A careful history, detailed clinical examination and follow up, and histopathology from the border of the lesion and the center are the keystones of diagnosis in pyoderma gangrenosum.[4,18]

HIV Kartagener’s syndrome

8. Associated Disease

Lung cysts Necrotizing sclerokeratitis PAPA syndrome Paroxysmal nocturnal hemoglobinuria ((Author: please confirm disease name?)) Phospholipid syndrome Primary biliary cirrhosis Sarcoidosis Vaquez disease Wegener’s granulomatosis PAPA = pyogenic arthritis, pyoderma gangrenosum and acne.


As described by Brunsting et al.,[1] pyoderma gangrenosum is commonly associated with inflammatory bowel disease. In larger series((Author: of how many patients?)), about 50% of patients show an underlying disorder((Author: please provide a reference)). Ulcerative colitis is found in 10 to 15% of patients; sometimes it is asymptomatic, in other patients the inflammatory processes of bowel and skin run a parallel course. Another associated disease is Crohn’s regional enteritis, with a frequency approximating that of ulcerative colitis. A 2.9% prevalence of pyoderma gangrenosum in patients with Crohn’s disease has been Am J Clin Dermatol 2002; 3 (3)


a

5

b

Fig. 4. Pyoderma gangrenosum in a patient with associated ulcerative colitis: (a) deep purulent ulcerations of the lower legs, (b) partial improvement after 8 days of alginate dressings and cyclosporine ((Author: in the text you mention low-dose. what dosage was administered?))

estimated, with no gender predilection.[24] Seronegative polyarticular arthritis and spondylitis are associated with both pyoderma gangrenosum and inflammatory bowel disease. A broad spectrum of lymphoproliferative disorders including leukemia, lymphoma and myelodysplastic syndrome has been described in patients with pyoderma gangrenosum (table II).[1,4,14,17,18] The association with an underlying disease is weakest in patients with vegetating ((Author: you have not used this term previously. Please define?))pyoderma gangrenosum.[18] Atypical pyoderma gangrenosum is more common in patients with malignancies.[24] 9. Treatment The treatment of pyoderma gangrenosum includes topical and systemic approaches. Since the course of the disease in patients is extremely variable, treatment modalities have to be adapted to the individual patient. 9.1 Topical Therapy

Topical treatment is important in any patient when ulcers have developed. Moist wound management is a cornerstone of topical wound management. It should aim to control exudation, improve auto-debridement, protect the surrounding skin and provide pain relief. Secondary infections have to be prevented and traumatization during dressing changes needs to be avoided. For superficial nonpurulent lesions, covering by a hydroactive dressing with a sufficient water handling capacity is recommended. Since most ulcers show a heavy exudate, hydrocolloids with their  Adis International Limited. All rights reserved.

characteristic disintegration and limited water-binding are less appropriate than foam dressings (like Allevyn®1, Smith & Nephew; and Cutinova®, Beiersdorf) or laminate dressings (like Tielle®, Johnson & Johnson; Combiderm®, ConvaTec; and Askina transorbent®, Braun-Petzold) composed of different layers to handle the exudate. In the case of sloughy or purulent covered lesions, semiocclusive dressings are contraindicated. Wet compresses with sterile saline solution or Ringer-lactate solution, or the new developments in dressings for prolonged irrigation, like Tenderwet® (Hartmann), can be applied.[25] Alternatively, hydrofiber or alginate dressings (like Algosteril Trionic®, Johnson & Johnson; Sorbasan®, Braun-Petzold; and Aquacel®, ConvaTec) are useful in controlling the exudate and improving wound odor[26,27] (figure 4). Relief of pain and improvement of odor have also been observed with plain yoghurt on compresses.[28] The topical use of disinfectants may irritate both the ulcers and the surrounding skin. Polyhexanide in Ringer-lactate solution has been proven to be well tolerated and efficient, whereas hydrogen peroxide can no longer be recommended as it is toxic for wound cells((Author: please provide references)). In patients with hyperthyreosis, the use of iodide-containing disinfectants is contraindicated because of systemic absorption and possible induction of hyperthyroid crisis((Author: please provide a reference and confirm rewording is acceptable)). Chlorhexidine can 1 Use of tradenames is for product identification purposes only and does not imply endorsement. Am J Clin Dermatol 2002; 3 (3)

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cause anaphylactic reactions; topical antibacterials should be avoided since their potential to sensitize is high and their efficacy is questionable.[29,30] Deep ulcerations may benefit from vacuum sealing; this improves granulation, but the commonly performed tacking of the occlusive foils necessary to cover the wounds can trigger ulcer spreading((Author: please provide a reference)). Granulation may also be improved with esterified hyaluronic acid, available as sheets or granulate. It is supposed to be used to rebuild the dermal matrix and improves the take rate for allogenic keratinocyte transplants.[31,32] For small flat lesions without secondary infection, topical high-potency corticosteroid lotion, ointment or cream is used. Topical corticosteroid therapy rarely induces disease remissions, except in patients with peristomal pyoderma gangrenosum. That is why local injections of triamcinolone are favored for other body sites((Author: what do you mean by other body sites?)).[33] Multiple injections are easily performed with the Dermojet® device. Infections are a contraindication for the use of corticosteroids. Tacrolimus (FK-506) is a new immunomodulator that has been used with success in topical formulation, in some patients.[34-36] Eight patients with peristomal pyoderma gangrenosum were successfully treated with 0.3% tacrolimus in carmellose sodium paste.[37] I have treated only one patient, who had ulcerating pyoderma gangrenosum, with the tacrolimus ointment as recommended by Petering et al.,[36] but failed to induce any response. Cyclosporine solution has been used in olive oil for topical treatment in one patient,[38] and intralesional injected cyclosporine in another patient.[39] The injections are quite painful. Despite the topical application, the action of topical or local ((Author: injection of?))cyclosporine is systemic because of resorption. Topical therapy with 1 to 4% disodium chromoglycate in aqueous solution several times a day or in combination with a hydrocolloid dressing was found to be useful by one set of authors[40] but not by another set.[41] The mechanism of chromoglycate action in pyoderma gangrenosum remains unclear. It has not been proven that this compound, in combination with hydrocolloids, is superior to hydrocolloids alone. Nicotine transdermal delivery systems applied on pyoderma gangrenosum ulcers and nicotine chewing gums have shown a beneficial anti-inflammatory effect.[42,43] Administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) is associated with wound contraction, increased keratinocyte proliferation and the activation of mononuclear inflammatory cells. GM-CSF, administered as a perilesional injection or topically applied, was shown  Adis International Limited. All rights reserved.

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to promote wound healing in patients with pyoderma gangrenosum.[44] The administration of GM-CSF or granulocyte colony-stimulating factor has also been associated with newly diagnosed pyoderma gangrenosum;[45] further studies have to be performed. Anecdotally reported topical treatments include 5aminosalicylic acid, potassium iodide, sucralfate, and nitrogen mustard.[14,18,37,46]

9.2 Systemic Therapy

For patients with a more widespread disease or a rapidly progressive course, systemic treatment is mandatory. Corticosteroids, for example prednisolone 100 to 200 mg/day (1 to 2 mg/kg of bodyweight), are widely used for initial therapy.[4,14,17,18] Initial high-dose therapy is attempted to prevent progression, as well as to stimulate rapid interruption of the inflammation process. In patients with more superficial and localized types of pyoderma gangrenosum, medium doses of corticosteroids may also work. In the presence of secondary infection, systemic corticosteroids should be combined with systemic antibacterials. Pulse therapy with suprapharmacological doses of corticosteroids (1g of methylprednisolone ((Author: at what frequency?))), act faster and can help to control the disease in patients with aggressive pyoderma gangrenosum variants.[47] Since this treatment may cause fatal adverse effects in patients with cardiovascular disease on diuretics((Author: please provide a reference)), careful patient selection is required. Cyclosporine is an immunomodulator that inhibits the activation of T lymphocytes and the early inflammatory response. Cyclosporine is a specific reversible inhibitor of the transcription process of interleukin-2 and other cytokines. Immunosuppressive therapy with cyclosporine has become an accepted treatment for patients with widespread pyoderma gangrenosum, after initial corticosteroids ((Author: in who initial therapy with corticosteroids has not been successful?))or in combination with corticosteroids. In many cases corticosteroids can be completely replaced by cyclosporine.[48,49] Originally, recommended doses of cyclosporine for the treatment of pyoderma gangrenosum reached 5 to 10 mg/kg of bodyweight, but hypertension and impairment of renal function occurred quite frequently((Author: please provide a reference)). The new formulation of cyclosporine (Sandimmun Optoral® or Neoral®) has an improved bioavailability. Low doses of cyclosporine (2 to 3mg/kg of bodyweight/day) have been shown to be effective in the treatment of pyoderma gangrenosum.[50] In my experience, most patients can be treated with low-dose therapy (figure 4). In patients whose disease does not respond to cyclosporine, a combination with other immunosuppressive drugs seems to be better tolerated than Am J Clin Dermatol 2002; 3 (3)


a

b Fig. 5. Deep purulent ulceration in a patient with idiopathic pyoderma gangrenosum: (a) relapse during combined corticosteroid and cyclosporine therapy, (b) improvement during intravenous human ((Author: recombinant?))immunoglobulin therapy.

an increased dose of cyclosporine. During therapy with cyclosporine it is necessary to control ((Author: closely monitor?))blood pressure and creatinine levels. Sulfa drugs are useful in patients with milder forms of pyoderma gangrenosum and are considered to be drugs of second choice (after corticosteroids and/or cyclosporine). The combination of corticosteroids with dapsone at a dosage of up to 200mg daily is a popular treatment. This therapy is only suitable for patients with normal glucose-6-phosphate dehydrogenase levels. Dapsone inhibits neutrophil migration and production of reactive oxygen species, and exerts a variety of other anti-inflammatory activities.[17,18,51] Met-hemoglobin levels should be controlled regularly ((Author: closely monitored?))during treatment with dapsone. Because of the association between smoking and increased met-hemoglobin levels, patients who smoke are at an  Adis International Limited. All rights reserved.

7

increased risk of this adverse event occurring((Author: please confirm that rewording is ok)). The addition of vitamin C ((Author: particularly in these patients or in all patients?))has been suggested to improve tolerability((Author: please provide a reference)). Clofazimine is a scavenger of hypochlorous acid, thus reducing the chlorination of proteins by neutrophils. Administration of the drug stimulates phagocytosis and superoxide production, clofazimine also has direct antibacterial activity. In my opinion the efficacy of clofazimine 300 to 400 mg/day is comparable to that of sulfa drugs such as dapsone. A common adverse effect is hyperpigmentation.[52] Thalidomide shows immunomodulatory activity such as suppression of tumor necrosis factor-α, basic fibroblast growth factor and neutrophil chemotaxis. Thalidomide has been used ((Author: with success?))in combination with corticosteroids in individual patients and in small series of patients.[53] In addition, sulfasalazine, rifampin, tetracyclines, vancomycin, mezlocillin, and minocycline have been reported to be useful in combination with corticosteroids.[17,18,51] Azathioprine (100 to 150 mg/day) is a cytotoxic drug usually employed for its corticosteroid-sparing effects. There is a delay of action of at least 2 to 4 weeks. Blood counts and transaminases should be monitored.[4,14,18] There is wide interpatient variability in azathioprine metabolism because of a common genetic polymorphism of thiopurine methyltransferase, a major metabolizing enzyme of azathioprine((Author: please provide a reference)). Azathioprine and sulfasalazine are a good choice when the underlying disease is ulcerative colitis or Crohn’s disease. Mycophenolate mofetil is an inhibitor of purine synthesis, selectively reducing the proliferation of T and B lymphocytes. With mycophenolate mofetil dosages of 2 mg/day there is a very low risk of renal and hepatic adverse effects. Mycophenolate mofetil has been used as monotherapy and in combination with cyclosporine for patients with disease that has been refractory to treatment.[54] Cytotoxic drugs have been used in patients with aggressive pyoderma gangrenosum. Among others, methotrexate,[55] cyclophosphamide,[56] and chlorambucil[57] have been investigated. These drugs are reliable in patients with a more aggressive disease course. Cyclophosphamide seems to be more efficient and less toxic when used as intravenous pulse therapy with ((Author: doses or an initial dose?))of 500 mg/m2 in the initial phase. Beneficial effects of these cytotoxic drugs are noted within 6 to 8 weeks, but relapse of the disease may occur after drug withdrawal. High dose intravenous immunoglobulins have been used for the treatment of chronic wounds, as treatment with this therapy Am J Clin Dermatol 2002; 3 (3)

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case report sheds light on the inflammatory mechanisms involved in pyoderma gangrenosum.[65] 9.3 Surgical Therapy

a

b Fig. 6. A patient with large ulceration pyoderma gangrenosum associated with

Crohn’s disease treated with split skin graft: (a) before treatment a purulent large ulceration with bluish border was present, (b) after split skin grafting and introduction of cyclosporine and prednisolone therapy, there was a marked improvement with a take of more than 90% of grafted area.

is associated with improved phagocytosis and opsonization.[58] γ-Globulin has also been reported to be effective for the treatment of pyoderma gangrenosum in some patients.[59,60] Dosages of human ((Author: recombinant?))immunoglobulins (up to 1g/kg of bodyweight/day) have been administered for several days with success, this therapy was in addition to corticosteroids and was repeated weekly or on a monthly base (figure 5). The list of treatments used in individual patients or small series of patients with pyoderma gangrenosum is long. Other therapies, including interferon-α (for hepatitis C–associated disease), colchicine, plasmapheresis as an adjunct to immunosuppressive therapy, and the use of hyperbaric oxygenation to improve wound healing in patients with the disease, have been reported.[61-64] Of particular interest is a recent case report describing the improvement of pyoderma gangrenosum during infliximab administration in a patient with recalcitrant Crohn’s disease. This  Adis International Limited. All rights reserved.

Surgery may be a significant trigger for pyoderma gangrenosum,[66] and even acupuncture may induce the disease in some patients,[67] an effect known as the pathergy phenomenon. Surgical procedures may be worthwhile for individual patients; however, any surgical procedure has to be done as an adjunct to concomitant immunosuppression and in patients with stable disease or partial remission. Autologous split-skin grafts have been used in patients with pyoderma gangrenosum of the breast and limbs, with variable success (figure 6). A major benefit of transplantation is the combination of pain reduction and improvement of granulation.[32,6871] A significant disadvantage of split-skin grafts is the necessity to create a new wound at the donor site. To reduce local trauma, autologous keratinocyte grafts have been developed from interfollicular epidermal[72,73] and outer root-sheath keratinocytes[74] and applied on ulcers in patients with pyoderma gangrenosum.[32,75,76] The cultivation of keratinocytes is time consuming. To cover an ulcer of about 70cm2, 3 to 4 weeks of cell culture is necessary. To ensure a good take rate, the ulcers have to be free of any infection, have low levels of exudate, very flat and with reduced inflammation. In these cases, autologous keratinocyte grafts are as effective as split-skin grafts, but the whole procedure is less invasive. New developments include the use of a keratinocyte delivery system based on an esterified hyaluronic acid membrane[32] and bioengineered allogenic skin (Graftskin®).[77] To ensure the best results, surgery should always be combined with immunosuppressive treatment independent from the grafting technique employed.[78] 10. Conclusion Despite considerable effort towards a better understanding of the disease, as well as the development of new treatment modalities, the course of pyoderma gangrenosum is still unpredictable. Both mild, limited disease and progressive, ‘malignant’ disease may occur. Traumatization of skin should be avoided. Long-term treatment may be necessary. The best way to treat ((Author: does this apply to all patients, or just those with severe forms of the disease?))pyoderma gangrenosum is to hospitalize the patient, and combine therapy of the underlying disease, topical wound management and systemic immunosuppression. Hopefully, more specific immunomodulators and bioengineered skin will support therapy in the future, even in patients with severe forms of the disease. Am J Clin Dermatol 2002; 3 (3)


Acknowledgments The author gratefully acknowledges the cooperation of Helga Konrad, Dr Theodor Karamfilov and Dr Kristin Liebold. This paper is dedicated to Professor Claus Seebacher, former director of the Department of Dermatology at Dresden-Friedrichstadt.

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22.

((Author: please confirm journal name, could it be Arch Belg Dermatol Syphiligr?)) Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma (ecthyma) gangrenosum: clinical and experimental observations in five cases occuring in adults. Arch Dermatol Syph 1930; 22: 655-80 Kuner N, Hartschuh W. Darstellung des Pyoderma gangraenosum in einem dermatologischen atlas des frühen 19: Jahrhunderts. Hautarzt 2000; 51: 519-23 Perry HO. Pyoderma gangrenosum. South Med J 1969; 62: 899-908 Van den Driesch P. Pyoderma gangrenosum: a report of 44 cases with follow-up. Br J Dermatol 1997; 137: 1000-5 Graham JA, Hansen KK, Rabinowitz LG, et al. Pyoderma gangrenosum in infants and children. Pediatr Dermatol 1994; 11: 10-7 Dick DC, Mackie RM, Patrick WJA, et al. Pyoderma gangrenosum in infancy. Acta Derm Venereol 1982; 62: 348-50 Fulbright RK, Wolf JE, Tschen JA. Pyoderma gangrenosum at surgery sites. J Dermatol Surg Oncol 1985; 11: 883-6 Su WPD, Schroeter AL, Perry HO, et al. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol 1986; 13: 323-30 Shaya S, Kindzelskii AL, Minor J, et al. Aberrant integrin (CR4; α xβ 2; CD11c/CD18) oscillation on neutrophils in a mild form of pyoderma gangrenosum. J Invest Dermatol 1998; 111: 154-8 Adachi Y, Kindzelskii AL, Cookingham G, et al. Aberrant neutrophil trafficking and metabolic oscillations in severe pyoderma gangrenosum. J Invest Dermatol 1998; 111: 259-68 Tanaka N, Fujioka A, Tajima S, et al. Elafin is induced in epidermis in skin disorders with dermal neutrophilic infiltration: interleukin-1 beta and tumour necrosis factor-alpha stimulate ist secretion in vitro. Br J Dermatol 2000; 143: 728-32 Wines ME, Lee L, Katari MS, et al. Identification of mesoderm development (mesd) candidate genes: comparative mapping and genome sequence analysis. Genomics 2001; 72: 88-98 Van Hale HM, Rogers RS, Zone JJ, et al. Pyostomatitis vegetans: a reactive mucosal marker for inflammatory disease of the gut. Arch Dermatol 1985; 1215: 94-8 Schwaegerle SM, Bergfeld WF, Senitzer D, et al. Pyoderma gangrenosum: a review. J Am Acad Dermatol 1988; 18: 559-68 Krüger S, Piroth W, Amo Takyi B, et al. Multiple aseptic pulmonary nodules with central necrosis in a patient with pyoderma gangrenosum. Chest 2001; 119: 977-8 Marie I, Levesque H, Joly P, et al. Neutrophilic myositis as an extracutaneous manifestation of neutrophilic dermatosis. J Am Acad Dermatol 2001; 44: 137-9 Prystowsky JH, Kahn SN, Lazarus GS. Present status of pyoderma gangrenosum. Arch Dermatol 1989; 125: 57-64 Powell FC, Su WRD, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996; 34: 395-409 Hurwitz RM, Haseman JH. The evolution of pyoderma gangrenosum: a clinicopathologic correlation. Am J Dermatopathol 1993; 15: 28-33 Winkelmann RK, Wilson-Jones E, Gibson LE, et al. Histopathologic features of superficial granulomatous pyoderma gangrenosum. J Dermatol 1989; 16: 12732 Park HJ, Kim YC, Cinn YW, et al. Granulomatous pyoderma gangrenosum: two unusual cases showing necrotizing granulomatous inflammation. Clin Exp Dermatol 2000; 25: 617-20 Bennett ML, Jackson JM, Jorizzo JL, et al. Pyoderma gangrenosum. A comparison of typical and atypical cases with an emphasis on time to remission: case review of 86 patients of 2 institutions. Medicine (Baltimore) 2000; 79: 37-46


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23. ((Author: is this an abstract/ letter or single page article?)) Burton JL. Sweet’s syndrome: pyoderma gangrenosum and acute leukaemia. Br J Dermatol 1980; 102: 239 24. Bernstein CN, Blanchard JF, Rawsthorne P, et al. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 2001; 96: 1116-22 25. Cooper P. TenderWet: an innovation in moist wound healing. Br J Nurs 1998; 7: 1232-5 26. Auböck J. Synthetic dressings. Curr Probl Dermatol 1999; 27: 26-48 27. ((Author: I have deleted Ulcus cruris as it does not conform to our house style, please confirm)) Wollina U. Moderne wunddressings: ein update. Vasomed 1997; 9 Suppl.: 148-52 28. Wollina U, Liebold K, Konrad H. Topical treatment of malignant wounds. Eur J Geriatrics 2001; 3: 118-21 29. Kramer A, Adrian V, Rudolph P, et al. Explanttest mit Haut und Peritoneum der neonatalen Ratte als prädiktiver Toleranztest für lokale anti-infektiöse Substanzen für Wunden und Körperkavitäten. Chirurg 1998; 69: 840-5 30. Wollina U. Contact allergy associated with topical treatment. In: Gebhardt M, Elsner P, Marks Jr JG, editors. Handbook of contact dermatitis. London: Martin Dunitz Publishers, 2000: 71-81 31. ((Author: please confirm journal name)) Ortonne JP. A controlled study of the activity of hyaluronic acid in the treatment of venous leg ulcers. J Dermatol Treat 1996; 7: 75-81 32. Wollina U, Karamfilov T. Treatment of recalcitrant ulcers in pyoderma gangrenosum with mycophenolate mofetil and autologous keratinocyte transplantation on a hyaluronic acid matrix. J Eur Acad Dermatol Venereol 2000; 14: 187-90 33. Goldstein F, Krain R, Thornton JJ. Intralesional steroid therapy of pyoderma gangrenosum. J Clin Gastroenterol 1985; 7: 499-501 34. Abu-Elmagd K, Van Thiel DH, Jegasothy BV, et al. Resolution of severe pyoderma gangrenosum in a patient with streaking leukocyte factor disease after treatment with tacrolimus (FK-506). Ann Intern Med 1993; 119: 595-8 35. Reich K, Vente C, Neumann C. Topical tacrolimus for pyoderma gangrenosum. Br J Dermatol 1998; 139: 755-7 36. Petering H, Kiehl P, Kapp A, et al. Pyoderma gangraenosum: erfolgreiche topische Therapie mit Tacrolimus (FK506). Hautarzt 2001; 52: 47-50 37. Lyon CC, Smith AJ, Beck MH, et al. Parastomal pyoderma gangrenosum: clinical features and management. J Am Acad Dermatol 2000; 42: 992-1002 38. Theissen U, Luger TA, Schwarz T. Erfolgreiche topische Anwendung von Cyclosporin A bei Pyoderma gangraenosum. Hautarzt 1996; 47: 132-5 39. ((Author: is this an abstract/ letter or single page article?)) Mrowietz U, Christophers E. Clearing of pyoderma gangrenosum by intralesional cyclosporin A. Br J Dermatol 1991; 125: 499 40. Langenbach N, Goetz A, Hohenleutner U, et al. Effectiveness of 4% disodium chromoglycate in the treatment of pyoderma gangrenosum. Acta Derm Venereol 1996; 76: 501-2 41. Anderson LL, Samlaska CP, Cardone JS, et al. Treatment of pyoderma gangrenosum with 4% cromolyn. Arch Dermatol 1994; 130: 1117-20 42. Wolf R, Wolf D, Ruocco V. The benefits of smoking in skin disease. Clin Dermatol 1998; 16: 641-7 43. Kanekura T, Kanzaki T. Successful treatment of pyoderma gangrenosum with nicotine chewing gum. J Dermatol 1995; 22: 704-5 44. Groves RW, Schmidt-Lucke JA. Recombinant human GM-CSF in the treatment of poorly healing wounds. Adv Skin Wound Care 2000; 13: 107-12 45. Ross HJ, Moy LA, Kaplan R, et al. Bullous pyoderma gangrenosum after granulocyte colony-stimulating factor treatment. Cancer 1991; 68: 441-3 46. Lyon C, Stapleton M, Smith A, et al. Topical sucralfate in the management of peristomal skin disease: an open study. Clin Exp Dermatol 2000; 25: 584-8 47. Johnson RB, Lazarus GS. Pulse therapy: therapeutic efficacy in the treatment of pyoderma gangrenosum. Arch Dermatol 1982; 118: 76-84 48. Matis WL, Ellis CN, Griffiths CEM, et al. Treatment of pyoderma gangrenosum with cyclosporine. Arch Dermatol 1992; 128: 1060-4

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O’Donnell B, Powell FC. Cyclosporin treatment of pyoderma gangrenosum. J Am Acad Dermatol 1991; 24: 141-3 Zumdick M, Goerz G, Schuppe HC, et al. Niedrig dosierte Cyclosporin-A-Therapie bei Pyoderma gangraenosum: erfahrungen bei 6 Patienten. Hautarzt 1995; 46: 697-701 Callen JP. Pyoderma gangrenosum and related disorders. Adv Dermatol 1989; 4: 51-70 Arbiser JL, Moschella SL. Clofazimine: a review of its medical uses and mechanisms of action. J Am Acad Dermatol 1995; 32: 241-7 Peuckmann V, Fisch M, Bruera E. Potential novel uses of thalidomide: focus on palliative care. Drugs 2000; 60: 273-92 ((Author: please supply correct page range i.e. is it 431-438?)) Michel S, Hohenleutner U, Mohr V, et al. Therapieresistentes Pyoderma gangraenosum: eine Behandlung mit Mycophenolatmofetil und CyclosporinA. Hautarzt 1999; 50: 438-1 Teitel AD. Treatment of pyoderma gangrenosum with methotrexate. Cutis 1996; 57: 326-8 Newell LM, Malkinson FD. Pyoderma gangrenosum: response to cyclophosphamide therapy. Arch Dermatol 1985; 113: 601-4 Burruss JB, Farmer ER, Callen JP. Chlorambucil is an effective corticosteroidsparing agent for recalcitrant pyoderma gangrenosum. J Am Acad Dermatol 1996; 35: 720-4 Wollina U, Looks A, Kammler HJ. Intravenous immunoglobulin therapy in dermatology; review and center experience. Anais Bras Dermatol (Rio de Janeiro) 1998; 73: 255-9 Gupta AK, Shear NH, Sauder DN. Efficacy of human immune globulin in pyoderma gangrenosum. J Am Acad Dermatol 1995; 32: 140-2 Dirschka T, Kastner U, Behrens S, et al. Successful treatment of pyoderma gangrenosum with intravenous human immunoglobulin. J Am Acad Dermatol 1998; 39: 789-90 Smith JB, Shenefelt PD, Soto O, et al. Pyoderma gangrenosum in a patient with cryoglobulinemia and hepatitis C successfully treated with interferon alfa. J Am Acad Dermatol 1996; 34: 901-3 Kaminska R, Ikaheimo R, Hollmen A. Plasmapheresis and cyclophosphamide as successful treatments for pyoderma gangrenosum. Clin Exp Dermatol 1999; 24: 81-5 Paolini O, Hebuterne X, Flory P, et al. Treatment of pyoderma gangrenosum with colchicine. Lancet 1995; 345: 1057-8 Wasserteh V, Bruce S, Sessoms SL, et al. Pyoderma gangrenosum treated with hyperbaric oxygen therapy. Int J Dermatol 1992; 31: 594-6


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Tan MH, Gordon M, Lebwohl O, et al. Improvement of pyoderma gangrenosum and psoriasis associated with Crohn disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 2001; 137: 930-3 MacKenzie D, Moiemen N, Frame JD. Pyoderma gangrenosum following breast reconstruction. Br J Plast Surg 2000; 53: 441-3 ((Author: is this an abstract/ letter or single page article?)) Castro-Duran J, Martin-Armada M, Jimenez-Alonso J. Pyoderma gangrenosum induced by acupuncture in a patient with ulcerative colitis. Arch Intern Med 2000; 160: 2394 Havlik RJ, Giles PD, Havlik NL. Pyoderma gangrenosum of the breast: sequential grafting. Plast Reconstr Surg 1998; 101: 1909-14 Cliff S, Holden CA, Thomas PR, et al. Split skin grafts in the treatment of pyoderma gangrenosum: a report of four cases. Dermatol Surg 1999; 25: 299-302 Hafner J, Trüeb RM. Management of vasculitic leg ulcers and pyoderma gangrenosum. Curr Probl Dermatol 1999; 27: 277-85 Alam M, Grossman ME, Schneiderman PI, et al. Surgical management of pyoderma gangrenosum: case report and review. Dermatol Surg 2000; 26: 1063-6 Gallico GG. Biologic skin substitutes. Clin Plast Surg 1990; 17: 519-26 Hunyadi J, Farkas B, Olah J, et al. Keratinocyte grafting; a new means of transplantation for full thickness wounds. J Dermatol Surg Oncol 1988; 14: 75-8 Limat A, Mauri D, Hunziker T. Successful treatment of chronic leg ulcers with epidermal equivalents generated from cultured autologous outer root sheath cells. J Invest Dermatol 1996; 101: 128-35 Dean SJ, Nieber S, Hickerson WL. The use of cultured epithelial autograft in a patient with idiopathic pyoderma gangrenosum. Ann Plast Surg 1991; 26: 1945 Limova M, Mauro T. Treatment of pyoderma gangrenosum with cultured keratinocyte autografts. J Dermatol Surg Oncol 1994; 20: 833-6 De Imus G, Golomb C, Wilkel C, et al. Accelerated healing of pyoderma gangrenosum treated with bioengineered skin and concomitant immunosuppression. J Am Acad Dermatol 2001; 44: 61-6 Rozen SM, Nahabedian MY, Manson PN. Management strategies for pyoderma gangrenosum: case studies and review of the literature. Ann Plast Surg 2001; 47: 310-5

Correspondence and offprints: Dr Uwe Wollina, Department of Dermatology, Hospital Dresden-Friedrichstadt, PO Box 120906, Dresden, 01008, Germany. E-mail: [email protected] ((Author: can we please publish your e-mail address?))

Am J Clin Dermatol 2002; 3 (3)