Etiology and Management of Pyoderma Gangrenosum

A Comprehensive Review


Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by painful, necrotic ulceration. It typically affects patients in the third to sixth decades of life, with almost equal incidence in men and women. PG occurs most frequently on the lower extremities. Five clinical variants are currently recognized: classic, bullous, pustular, vegetative, and peristomal types. Half of PG cases are seen in association with systemic disease. Mimickers include infection, vascular insufficiency ulcers, systemic vasculitides, autoimmune disease, cancer, and exogenous tissue injury, among others. PG is often a diagnosis of exclusion, as there are no specific laboratory or histopathologic findings to confirm the diagnosis. PG thus presents many clinical challenges: it is difficult to diagnose, is frequently misdiagnosed, and often requires a work-up for underlying systemic disease. Successful management of PG typically requires multiple modalities to reduce inflammation and optimize wound healing, in addition to treatment of any underlying diseases. Prednisone and cyclosporine have been mainstays of systemic treatment for PG, although increasing evidence supports the use of biologic therapies, such as tumor necrosis factor-a inhibitors, for refractory cases of PG. Here, we review the clinical presentation and pathophysiology of PG, as well as its associated conditions, diagnostic work-up, and management.

1. Definition and Clinical Presentation

Pyoderma gangrenosum (PG), first described by Brocq[1] and named by Brunsting et al.[2] in 1930, is a rare, ulcerating, neutrophilic dermatosis primarily affecting patients aged 25–54 years, without a clear gender predilection.[3,4] Epidemiologic data establishing disease incidence have yet to be published. A few single-center cohorts provide the best available estimates: one regional dermatology clinic saw 15 cases of PG out of 0.5 million patients over the course of 10 years.[4] At the Mayo Clinic in Rochester,MN, USA, 180 diagnoses of PG were made over 53 years.[5] In a survey study of 31 619 patients with chronic leg ulcers, PG represented 3% of cases.[6]

A PG lesion typically starts as a tender nodule, plaque, or sterile pustule that enlarges and erodes, over a course of days, into a sharply marginated ulcer with undermined, violaceous borders and a surrounding zone of erythema (figure 1); pain is a characteristic feature.[7] The skin and subcutis become necrotic, creating a friable wound bed often with a hemorrhagic or purulent exudate, sometimes extending as deep as muscle.[2] Cribiform or ‘sieve-like’ atrophic scars often form as the lesions heal. Lesions typically are multiple and recurrent,[8] and occur at areas of trauma in 25–50% of cases, a process known as pathergy (figure 2).[3]

Fig. 1

Pyoderma gangrenosum (PG) lesions. (a) PG ulcer in a young female patient with IgA vasculitis. (b) Cribiform PG ulcer associated with inflammatory bowel disease and lymphoma. Early pustular (c) and late ulcerative (d) lesions of PG in a female patient with inflammatory bowel disease and overlap syndrome of hidradenitis suppurativa and PG.

Fig. 2

(a) Extensive pyoderma gangrenosum ulcer of the leg associated with elective saphenous vein phlebectomy, exacerbated by repeated surgical wound debridement. (b) Close-up view demonstrates a violaceous, undermined border with surrounding erythema. Photograph courtesy of Michael Rosenblum, MD, PhD and Lindy P. Fox, MD.

PG lesions in adults most frequently affect the lower extremities; any anatomic site can be affected.[3,8] In children (approximately 4% of cases), PG typically involves the lower extremities, buttocks, and perineal region, as well as the head and neck.[9] PG may also involve extracutaneous sites such as the eye (scleritis and orbital inflammation[10]), the lungs (aseptic pulmonary nodules[11]), the spleen,[10] and the musculoskeletal system in the form of sterile pyoarthrosis[12] and neutrophilic myositis.[13]

There are currently five widely recognized subtypes of PG[4] (reviewed in table I): classic (ulcerative), bullous,[20] pustular,[16] vegetative,[14] and peristomal.[1719] Cases of PG induced by drugs such as isotretinoin and sunitinib have been reported[2124] but are generally not regarded as a distinct variant.

Table I

Subtypes of pyoderma gangrenosum

2. Pathophysiology

The pathophysiology of PG remains poorly understood, though is now believed to involve loss of innate immune regulation and altered neutrophil chemotaxis. Earlier hypotheses incorporated ideas of occult bacterial infection,[2] circulating autoantibodies,[3] or the Shwartzman reaction[25,26] (endotoxin-induced thrombosis with tissue necrosis). Decades of investigation have failed to support any of these initial hypotheses; however, a number of lines of evidence have strengthened the prevailing hypotheses of disease etiology, as outlined below.

2.1 Neutrophilic Dermatosis

The absence of evidence for infection, and the predominance of neutrophils in PG lesions, justifies its classification as a neutrophilic dermatosis, a spectrum that also includes Sweet syndrome (acute febrile neutrophilic dermatosis), bowel-bypass syndrome, dermatitis herpetiformis, erythema elevatum diutinum, subcorneal pustular dermatosis, and Behcet disease.[27] On biopsy, PG is characterized by the presence of inflammatory dermal infiltrates composed of mature neutrophils.[12] Although the neutrophils appear microscopically normal, a number of studies have demonstrated functional abnormality of these cells in PG. Abnormal neutrophil trafficking was described in one patient with PG with increased integrin CR3 and CR4 expression and dysregulated integrin signaling.[28] The importance of neutrophil dysregulation in the pathogenesis of PG is reinforced by the clinical response to antineutrophilic agents such as colchicine and dapsone, which disrupt neutrophil chemotaxis and phagocytosis.[29,30]

2.2 Autoinflammatory

Building upon the evidence for neutrophil dysfunction, a growing body of data favors the hypothesis that PG is a systemic autoinflammatory disease resulting from dysregulated innate immunity.[31] The association of PG with known autoinflammatory diseases such as Crohn disease and Behcet disease,[32] as well as the elevation in markers of systemic inflammation such as erythrocyte sedimentation rate[33] even in idiopathic PG, argue in favor of PG as a systemic autoinflammatory process. This is further supported by the requirement for systemic therapy in many cases of PG, and the discordance in disease activity between PG and its associated systemic diseases.[32] Recently observed associations between PG and another cutaneous disorder, hidradenitis suppurativa, supports the notion that both are on a spectrum of autoinflammatory syndromes,[34,35] or perhaps a convergent skin manifestation shared by a number of systemic illnesses.

2.3 Genetic

Rare familial forms of PG have been reported.[36,37] The recently described PAPA syndrome (pyogenic sterile arthritis, PG, and acne, Online Mendelian Inheritance in Man [OMIM]: 604416) is an autosomal dominant autoinflammatory disorder initially mapped to chromosome 15q.[38,39] PAPA syndrome arises from mutations in the gene encoding proline/serine/threonine phosphatase-interacting protein 1 (PSTPIP1; also known as CD2 antigen-binding protein 1, CD2BP1) on chromosome 15q24–25.1.[40] PSTPIP1 protein binds to pyrin, a regulator of the cryopyrin inflammasome. Mutations in PSTPIP1 may result in dysregulation of the cryopyrin inflammasome, activating interleukin (IL)-1β cytokine production and ensuing inflammation.[41] Although its relevance remains unclear for idiopathic PG cases, this discovery helps elucidate a potential pathway by which inflammation may be triggered in PG. PG has also been associated with other genetic diseases of immunity, including chronic granulomatous disease,[42] leukocyte adhesion deficiency,[43] and complement C2 and C4 deficiency.[44]

2.4 Cytokines

Various cytokines essential for leukocyte signaling may have a role in PG. IL-8 is an important neutrophil chemokine that is over-expressed in PG. PG-like ulcers have been induced in human skin xenografts transfected with recombinant IL-8.[45] IL-16 also functions in neutrophil chemotaxis. Its gene maps to 15q25 and, like IL-1β, may be over-expressed in PAPA syndrome.[41] A few cases of PAPA syndrome have reported improvement in PG with the IL-1 inhibitor anakinra, highlighting the importance of IL-1 in the pathogenesis of PG in that syndrome.[46]

3. Associated Conditions

Emerging evidence of the clinical efficacy of tumor necrosis factor (TNF) alpha inhibitor therapy for the treatment of PG strongly suggests a key role for this cytokine in this disease. PG is associated with underlying systemic diseases in approximately 50% of patients,[47,48] though association rates as high as 78% have been reported;[3] the remainder of cases are considered idiopathic. Inflammatory bowel disease (IBD), arthritis, and hematologic disorders are the most common disease associations. Although in most cases PG was diagnosed after the associated disease, it may also precede or be the presenting sign of an underlying disease. The courses of the two diseases are sometimes, but not necessarily, parallel.[3,32]

To fully characterize the spectrum of associated diseases, a comprehensive search of the English literature on PG was performed on 23 December 2010 using PubMed with the keywords ‘pyoderma gangrenosum.’ In order to identify the most consistent and plausible disease associations, single-reported associations were excluded, with the final data set limited to case series, defined as (i) a report of two or more cases of an associated disease or (ii) an aggregated patient report including some individuals with a given associated disease and some unaffected. We have adapted the classification schema for grouping the most frequently observed diseases by type, as proposed by Bennett et al.[47] An overview of the results is provided in table II and an individual discussion of the most commonly associated conditions follows in sections 3.1–3.3. Also included in table II are less frequent and possibly coincidental associations, such as hidradenitis suppurativa, systemic lupus erythematosus, and HIV, whose prevalence in association with PG is likely similar to that seen in the general population.[34,47,66,82]

Table II

Pyoderma gangrenosum disease associationsa

3.1 Inflammatory Bowel Disease

IBDs such as Crohn disease and ulcerative colitis (UC) are the systemic diseases most frequently reported in association with PG, with 214 reports found in our review. This association was seen in up to 41% of PG cases published in the past 3 decades.[62] However, in a population-based case series from the Mayo Clinic, Rochester, MN, USA, PG occurred in 0.48% of patients with UC and 0.33% of patients with Crohn disease,[3] suggesting over-representation ofIBD in published PG case series. A more recent prospective cohort study of 2402 French patients with IBD found PG in 0.75% of their patients, with no association between severity of IBD and presence of PG.[83] In the setting of IBD, the fluctuation of disease activity of PG may parallel that of IBD,[32] though frequently it does not.[8,84] However, the case for a related etiology is strengthened by reports of total proctocolectomy in a PG patient with UC leading to resolution of the PG. In one case series, PG lesions improved in all nine patients with UC following total proctocolectomy.[3]

3.2 Arthritis

PG is frequently associated with various arthritides, most commonly seronegative arthritis of a single, large joint,[85] though rheumatoid arthritis and ankylosing spondylitis are also common.[3,47] In our review, 83 cases were reported. An association as high as 37% was reported in one series.[3] The clinical severity of the arthritis is unrelated to PG activity.[4] While there is a significant subset of PG patients affected by both IBD and arthritis,[62,69] arthritis is more frequently seen in non-PG-associated IBD.

3.3 Hematologic Abnormalities, Paraproteinemias, and Malignancy

Hematologic abnormalities and hematologic malignancies (excluding paraproteinemias) were seen in 35 reports in our review, with 36 cases of paraproteinemia reported. Monoclonal gammopathy, most frequently IgA,[74] is the most common associated paraproteinemia with the reported association rate of 18%.[3] Though they usually remain clinically benign, these gammopathies occasionally progress to myeloma;[74] the likelihood of progression in PG-associated versus non-PG-associated monoclonal gammopathy has not been studied. Classic, ulcerative PG is the most common variant seen in monoclonal gammopathy, though bullous PG is seen in myeloma patients.[47] A variety of other hematologic abnormalities have been reported in association with PG, including polycythemia vera,[3,86] agnogenic myeloid metaplasia,[87,88] and essential thrombocythemia.[89] Two interesting cases of leukemoid reaction (white blood cells >50 000/uL) with fever and elevated neutrophil precursors as the initial presentation of severe PG were recently reported for the first time; all infectious cultures were negative and the patients failed to respond to initial antibiotic therapy.[90]

Hematologic malignancy is seen in up to 7% of PG cases, with acute myeloid leukemia (AML) being the most common subtype.[71] Most cases of leukemia were preceded by a hematologic abnormality such as myelodysplastic syndrome. While 30% of all paraneoplastic PG is of the previously described bullous subtype,[20] in leukemia, two-thirds of PG is bullous. PG lesion development portends a poor prognosis in AML, with a 1-year mortality rate as high as 75%[71,91] versus 67% in all AML patients.[92] This clinical observation underscores the need for an expeditious and thorough work-up for hematologic malignancy in any patient presenting with bullous PG lesions. Similarly, development of PG in the setting of myelodysplastic or myeloproliferative syndrome may herald impending malignant transformation.[71] Improvement of bullous PG has been reported with the treatment of the underlying malignancy.[73,93] This may be explained by the presence of a leukemic cell infiltrate in the skin seen in some bullous PG lesions associated with leukemia.[94,95]

4. Diagnosis

PG remains a clinical diagnosis; it lacks specific serologic or histologic markers. Although no clinical criteria have been formally adopted, one proposed set requires the fulfillment of two major criteria: (i) rapid progression (margin expansion of 1–2 cm per day, or 50% increase in ulcer size within 1 month) of a painful, necrolytic, cutaneous ulcer with an irregular, violaceous, and undermined border; and (ii) exclusion of other causes of cutaneous ulceration; and at least two minor criteria, including (a) a history suggestive of pathergy or a clinical finding of cribiform scarring, (b) systemic diseases associated with PG, (c) histopathologic findings (sterile dermal neutrophilia ± mixed inflammation ± lymphocytic vasculitis), and (d) treatment response (rapid response to systemic corticosteroid treatment).[7]

PG is also a diagnosis of exclusion: it is crucial to rule out other etiologies of ulcers, especially infectious causes.[96] The differential diagnosis is broad (reviewed in table III). Misdiagnosis of PG as another condition is frequent and may be harmful to patients. Well demarcated ulcers may be presumed to represent factitial dermatitis, potentially causing delay in treatment or psychological distress.[97] PG may also be mistaken for infection and subjected to wound debridement, which can provoke pathergy and exacerbate disease, or result in limb amputation.[98,99] A recent study suggests that as many as 10% of PG cases are actually misdiagnoses. Actual diagnoses, delayed on average by 10 months, included vascular disease (occlusive or venous insufficiency), vasculitis, malignancies, infections, drug-induced or exogenous tissue injury, and manifestations of other autoimmune diseases.[33]

Table III

Common differential diagnoses of pyoderma gangrenosum

Maintaining a high index of suspicion for PG is crucial to making the diagnosis. The diagnosis of PG should be considered in patients whose wounds are painful, rapidly expanding, non-healing and unresponsive to antibiotics, or worsening with surgical debridement. Vigilant monitoring for PG is also appropriate in any patient with a frequently associated systemic disease, such as IBD, arthritis, or hematologic disorder, presenting with new skin lesions.

The minimum evaluation should include a complete history, physical examination, and skin biopsies. A thorough patient history should clarify the progression of lesions, pathergy, recent exposures, and results of prior interventions attempted. A complete physical examination is necessary to reveal lesion morphology, define all areas of involvement, and assess for evidence of concurrent systemic disease. Skin biopsies are essential both for histologic examination with routine hematoxylin and eosin and special stains for infectious organisms, as well as for culture of bacteria, viruses, fungi, and atypical mycobacteria. Direct immunofluorescence studies may be helpful to exclude autoimmune skin disease or vasculitis (though findings are neither sensitive nor specific for PG).[100] Direct immunofluorescence studies show IgM, C3, and fibrin deposits in blood vessels of the papillary and reticular dermis in a majority of PG biopsy specimens.[100,101]

In obtaining a biopsy specimen, a deep elliptical incisional biopsy is preferable over a punch biopsy, with the specimen including a portion of the lesion’s edge and encompassing the subcutis.[33,100] Concern for inducing pathergy should not preclude the initial biopsy as it is essential to exclude other diagnoses, especially infection. Although nonspecific, the histopathology of PG is useful for exclusion of other conditions. The initial lesion, prior to ulceration, shows a deep suppurative, often folliculocentric inflammation with dense neutrophilic infiltrates, and a leukocytoclastic vasculitis is often present.[100] The undermined border of an ulcer shows a mixed, neutrophil-predominant, inflammatory infiltrate and the base of the lesion typically shows evidence of necrosis and hemorrhage. In a specimen taken from erythema surrounding a PG ulcer, necrosis of thrombosis of dermal or pannicular blood vessels may be seen, with a lymphocyte-predominant infiltrate.[7] Edema and lymphocytic vasculitis may also be present.

5. Work-Up

Experts recommend that a reasonable search for associated conditions is warranted in the evaluation of every case of PG,[4,32,47] though data are lacking on the predictive value of these tests. It is imperative to exclude infection or malignancy as part of the initial diagnostic work-up, especially if the patient will undergo systemic immunosuppression. No formal guidelines exist, but the emerging consensus for a work-up is presented here. Routine laboratory tests such as complete blood count with differential, electrolytes, urinalysis, and liver function tests may be helpful as an initial screen for hematologic disorders, liver or kidney dysfunction related to a variety of possible associated conditions, and hepatitis. Additional studies are helpful in excluding systemic disorders: anti-nuclear antibody, coagulopathy panel including antiphospholipid antibody test, cryoglobulins, rheumatoid factor, and circulating antineutrophil cytoplasmic antibodies. Further work-up for associated conditions may include chest x-ray (for infections or systemic vasculitis), fecal occult blood test and sigmoidoscopy or colonoscopy for IBD, and evaluation for hematologic disease (serum protein electrophoresis, urine spot protein or urine protein electrophoresis, immunofixation electrophoresis, peripheral smear, and bone marrow biopsy), especially in cases of bullous PG.[47,93,102] Infectious causes should be excluded including HIV, hepatitis serologies, and rapid plasma reagin, if risk factors exist.

A thorough neurologic exam should be performed. Radiologic studies may help exclude underlying osteomyelitis, and Doppler ultrasound can be useful in cases where vascular occlusion or insufficiency is suspected. Serum levels of iodide and bromide may help rule out halogenodermas.[47] Though nonspecific, elevated erythrocyte sedimentation rate and a serum neutrophilia are often seen with PG.[33]

6. Treatment

There is no gold standard for the treatment of PG. PG has both a systemic inflammatory component and a wound component, thus an effective treatment strategy must address both processes.[47] A combination of local wound care, topical, and/or systemic therapy is ideal, as proposed in our treatment algorithm (figure 3). In order to synthesize this treatment algorithm, a comprehensive search of the English literature for PG was performed on 20 January 2012 using PubMed with the keywords ‘pyoderma gangrenosum’ alone and in combination with ‘treatment,’ ‘refractory,’ ‘corticosteroids,’ ‘cyclosporine,’ ‘topical,’ ‘biologics,’ ‘therapy,’ and ‘wound care.’

Fig. 3

Diagnostic and therapeutic algorithm for pyoderma gangrenosum (PG). H&E = hematoxylin and eosin; IVIG = intravenous immunoglobulin; VAC = vacuum-assisted closure. Level I = prospective controlled trials; Level II = retrospective studies, small uncontrolled trials, large case series, many case reports; Level III = small case series or single case reports.

Goals of therapy are to control inflammation, reduce pain, optimize wound healing, and to minimize exacerbating factors. Treatment decisions should be made based on the size, number, location, and type of PG lesions, the progression of lesion formation, and the presence of an underlying disease. It is important to measure and record the size and depth of the lesion at each clinical evaluation. The initial approach should begin with optimizing wound care, achieving pain control, topical therapy, and the use of antimicrobial or anti-neutrophilic agents, especially for cases in which a diagnostic work-up is ongoing to exclude occult infection or malignancy. Systemic immunosuppression should be considered, especially in the setting of rapidly evolving PG.

PG lesions are almost universally painful. Pain management should include both regular pain level monitoring and judicious use of NSAIDs, opioids, and pain specialist and psychiatric consultants as needed for patients affected by chronic pain or depression.[103] When monitoring therapy, early relief of pain may be the first sign of healing before evidence of ulcer re-epithelialization.

Lesions of PG are often refractory to treatment and require multiple trials of medications or concomitant use of multiple medications before an effective therapy is found. One retrospective analysis noted an average of 12 months to healing in 86 patients with PG.[47] Physicians must set realistic expectations, maintain close follow-up, and create individualized therapeutic strategies. Smoking cessation, glycemic control in diabetes mellitus, optimizing nutrition, and minimizing edema (if present, as in venous insufficiency) may be important adjunctive interventions. The effects of smoking cessation on PG are controversial yet noteworthy. Multiple, large, retrospective and prospective studies demonstrate increased rates of wound infection and reduced rates of healing of post-operative wounds in smokers.[104] In contrast, there is evidence that topical nicotine may be beneficial in refractory PG, as reported in one case of an IBD patient with PG ulcers completely resolving with nicotine patches[105] and two cases of PG successfully treated with topical nicotine cream.[106]

6.1 Wound Care

Optimizing wound care is essential for the successful treatment of PG. Moisture-retentive occlusive dressings such as films and hydrogels are recommended for chronic wounds as they increase the rate of re-epithelialization, promote angiogenesis and collagen synthesis, and provide a barrier to infection.[107] However, these dressings may not be appropriate for highly exudative lesions as they can trap excessive moisture, leading to maceration of surrounding skin. In these lesions, more absorptive dressings such as hydrocolloids, foams, and alginate fibrous dressings or the use of iodine cadexomer starch gel pastes under dressings are more appropriate.[107] Wet to dry dressings should be avoided, as the debridement associated with dressing removal may trigger pathergy. The area around the wound can also be susceptible to irritation or allergy due to adhesive tape and topical antibiotic ointments. Barrier ointments including zinc oxide and petrolatum can help to protect these areas. Layering petrolatum-impregnated gauze over the topical agents and the peripheral edges of the ulcer may prevent trauma caused by overlying bandages. Compression can be useful if edema is present and there is no evidence of arterial insufficiency.[108]

It is imperative to monitor for signs of infection including fever, skin warmth, edema, erythema and lymphangitic streaking, foul odor, increased drainage, and pain. Topical antimicrobials such as mupirocin ointment are effective for Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, while topical metronidazole is effective for anerobic organisms. Silver sulfadiazine is effective for many common skin pathogens including Gram-negative bacilli; however, it may have toxic effects on keratinocytes.[107] Topical antimicrobials such as bacitracin and neomycin commonly induce contact dermatitis and should be avoided.[109] Topical antimicrobials can lead to bacterial resistance and delayed wound healing with inappropriate use, and should be utilized only when clinically significant infection is confirmed and not as empiric therapy.[110] Acetic acid soaks may be helpful to limit Pseudomonas aeruginosa biofilm development. If there is evidence of a deeper tissue infection, such as cellulitis or lymphangitis, appropriate oral antibiotics should be prescribed, guided by bacterial culture and antibiotic susceptibility data.

6.2 Topical Medications

Topical medications are important in the treatment of PG both as monotherapy for mild and superficial lesions and also as adjuncts to systemic treatment. Topical therapies offer the benefit of fewer adverse effects and contraindications compared with systemic regimens; however, they require frequent application, sometimes several times a day. Although there is a paucity of literature regarding topical therapy for PG, most authors agree that topical corticosteroids, topical tacrolimus, and topical cyclosporine are important components of the therapeutic algorithm.[102,111116] Investigators recommend the use of topical agents specifically at the inflamed border of the ulcer and not within the ulcer base.

In one of the few comparative trials in the literature on the treatment of PG, 24 patients with peristomal PG were treated with either topical tacrolimus 0.3% or topical clobetasol propionate 0.05%.[117] Seven of 11 patients in the tacrolimus group had complete healing of their lesions compared with 5 of 13 in the clobetasol group (no p-value given). In this study, complete healing with tacrolimus occurred in an average of 5.1 weeks versus 6.5 weeks with clobetasol (not statistically significant) and tacrolimus was more effective in PG lesions greater than 2cm(p < 0.05).[117] Caution should be advised when using topical tacrolimus as it can be highly absorbed through ulcerated tissue; serum tacrolimus levels have been shown to be equivalent to those achieved in systemic tacrolimus administration even when applied to limited (<5%) body surface area.[118] Topical cyclosporine (ophthalmic preparation) may not have similar concerns for systemic absorption, as several reports indicate serum cyclosporine levels in the subtherapeutic range and minimal adverse effects with topical use.[112,116]

Additional reports describe success with other topical agents. 5-Aminosalicyclic acid is the active component of sulfasalazine, which is commonly used to treat IBD. One report describes full healing of a PG lesion in a patient with Crohn disease after topical application of 10% 5-aminosalicylic acid for 5 weeks.[119] Additionally, Braun-Falco et al.[120] reported a case of PG with accelerated healing after application of the topical platelet-derived growth factor, becaplermin. One percent sodium cromoglycate has also been reported to be effective in a case series of five patients with PG with complete healing of all lesions within 5–8 weeks.[121] Cromoglycate may be effective in wound healing through inhibition of mast cell degranulation and platelet activation, and down-regulation of neutrophil chemotaxis.[121,122] Chlormethine (mechlorethamine or nitrogen mustard) is an alkylating agent often used in cancer therapy and has immunosuppressive and anti-inflammatory properties; Tsele et al.[123] reported a single case of complete resolution of a PG lesion with 20% topical nitrogen mustard.

6.3 Intralesional Therapy

Moschella[124] first reported the use of intralesional corticosteroids (6 mg/mL) in PG with complete healing in 21 days. Intralesional corticosteroids have since been described as a useful adjunct to systemic treatment for PG. Various concentrations (up to 40 mg/mL) of corticosteroids and at varying dosing schedules have been used successfully in PG according to the literature.[125] Two unusual cases of deep retrosternal and maxillary sinus PG were treated successfully with dexamethasone flushes via catheter.[76] Intralesional corticosteroids should be used with caution as too frequent injections or an excessively high concentration of corticosteroid can lead to pathergy and disrupt wound healing.[110] Intralesional injections every 4–6 weeks likely balances pathergy risk with the anti-inflammatory benefits of this treatment. Intralesional cyclosporine has also been reported to be effective in healing lesions of PG in a single patient.[126]

6.4 Surgery

The role of surgical treatment in PG is controversial as 25–50% of PG lesions demonstrate pathergy and theoretically could worsen with surgical intervention.[108,127] Nonetheless, there are reports of excellent outcomes after surgery including the use of gentle debridement, a free flap to cover a large lesion, and the use of cultured keratinocyte autografts.[128130] Split-thickness skin grafting has been shown to alleviate pain in PG.[108] In general, surgical intervention should be considered on a case-by-case basis and should only be used as an adjunct to anti-inflammatory treatment.

Strategies to prevent pathergy or disease exacerbation include ensuring the patient’s PG is clinically quiescent prior to surgery.[131133] Systemic therapy should be tapered slowly postoperatively, as abrupt cessation has been shown to result in recurrence.[131,133] Pathergy may be avoided by the use of subcuticular sutures or surgical tapes or glues as alternatives to suturing.[132]

Reported adjuncts to surgery in PG include the use of wound vacuum-assisted closure (VAC) devices, with two case reports demonstrating healing in patients with stable PG.[130] VAC devices utilize subatmospheric pressure applied to the wound surface leading to reduction of local edema, increased perfusion, and enhanced cellular proliferation. Hyperbaric oxygen has also been postulated as an effective adjunct to surgery in PG by increasing oxygen delivery to the ulcer.[110]

6.5 Systemic Treatments

Effective treatment of PG may require systemic therapy. Choice of agent includes consideration of potential adverse effects, the medical history and general health of the patient, and in relevant cases, the patient’s underlying disease. Whereas corticosteroids and cyclosporine were previously considered first-line treatments, the emergence of TNFα inhibitors is transforming the therapeutic ladder, with infliximab being the only systemic agent with level I evidence supporting its use for the treatment of PG.

6.5.1 Anti-Neutrophilic Therapies

Colchicine has anti-mitotic and immunomodulatory properties by interfering with neutrophil chemotaxis and phagocytosis and has demonstrated efficacy as an adjunct to corticosteroid therapy.[134] It was also used successfully as a monotherapy at a dosage of 0.6 mg three times a day in a case of penile PG.[29]

The mechanism of action of sulfonamides and sulfones is not completely understood but likely stems from inhibition of neutrophil chemotaxis. Dapsone is effective in other neutrophilic disorders such as Sweet syndrome, erythema elevatum diutinum, and subcorneal pustular dermatosis. Alone or in combination with corticosteroids, dapsone has been used successfully in PG at a dosage of 50–200 mg/day.[30,135,136] Dapsone was used successfully as a monotherapy in a patient with PG and Behcet disease.[137] Adverse effects include methemoglobinemia, anemia, and neuropathy. Topical dapsone has also recently been reported to be effective in improving peristomal PG.[138] Topical application appears to cause significantly lower (100-fold less) systemic levels of dapsone and its metabolites, likely protecting against dose-dependent hematologic reactions.[139]

6.5.2 Antimicrobials

Minocycline and other tetracyclines exhibit anti-inflammatory properties by decreasing neutrophil chemotaxis. One report of four cases showed successful treatment with minocycline 200–300 mg/day with response noted in weeks.[140] Clofazimine is another antimicrobial agent with anti-inflammatory properties, with conflicting reports of its efficacy in PG.[110]

6.5.3 Corticosteroids

The literature demonstrates that systemic corticosteroids (prednisone 0.5–1 mg/kg/day, methylprednisolone up to 0.8 mg/kg/day) are effective in a large number of cases and are a common first-line systemic therapy.[110,141,142] Response is usually rapid (2–3 days), halting lesion progression and preventing development of new lesions.[103] Long-term corticosteroid use is limited by many common and serious adverse effects including osteopenia, weight gain, glaucoma, cataracts, hyperglycemia and diabetes, Cushing syndrome, immunosuppression, adrenal insufficiency, and corticosteroid psychosis. One common treatment strategy utilizes systemic corticosteroids as initial therapy, with rapid transition to a corticosteroid-sparing agent once disease control is achieved.[110,141] Pulsed-dose corticosteroids can also be used, but should be reserved for rapidly progressive disease given the potential for sudden electrolyte shifts and cardiac arrhythmias.[4,62] In one study, six of eight patients healed with methylprednisolone 1 g/kg pulse therapy daily for 3–5 days followed by prednisone 40–60 mg daily with tapering as the lesions healed (average of 5.5 months).[62] As corticosteroid therapy may be extended, prophylaxis for osteoporosis including calcium, vitamin D, and bisphosphonates (if not contraindicated), as well as for Pneumocystis carinii pneumonia, should be considered.

6.5.4 Cyclosporine

Cyclosporine is also considered first-line treatment for PG and may be particularly useful in rapidly progressive disease (especially when given intravenously). Two case series demonstrated complete healing in 13 patients treated with oral cyclosporine at a dosage of 3–10 mg/kg/day.[143] The only reported adverse effect in both studies was tuberculosis reactivation in one patient. Another series of 11 patients with corticosteroid-refractory PG and IBD were treated with intravenous cyclosporine 4 mg/kg/day for 7–22 days (followed by oral cyclosporine 4–7 mg/kg/day), demonstrating epithelialization of lesions in a mean time of 1.4 months with no reported adverse effects. Additionally, all seven patients with active IBD symptoms at the time of cyclosporine initiation went into remission, suggesting cyclosporine is an effective choice for PG in the setting of IBD.[144] Adverse effects include hypertension, hepatotoxicity, tremor, electrolyte abnormalities, myelosuppression, increased risk of infection, and renal toxicity; it is generally not recommended for use longer than 1 year at a time.[145] Thus, some argue that cyclosporine, like prednisone, should be used for acute control of PG or in idiopathic disease, but is not appropriate as a long-term maintenance therapy for patients with chronic underlying conditions such as IBD.[103]

6.5.5 Biologic Therapy

Biologic agents are emerging as useful treatment options for PG and are frequently used to treat specific associated conditions including Crohn disease. Infliximab, an anti-TNFα monoclonal antibody binding both soluble and membrane-bound TNFα, is the only biologic that has shown efficacy in classic PG in a randomized, double-blind, controlled trial (level I evidence).[146] Thirty patients were given either infliximab 5 mg/kg or placebo. At 2 weeks, 6 of 13 patients in the infliximab group showed improvement in the severity and/or size of ulcers, versus only 1 of 17 in the placebo group. After 2 weeks, the 16 non-responders in the placebo group were switched to infliximab and by week 6, 20 of 29 patients treated with infliximab demonstrated improvement in their PG lesions, with 6 of 29 showing complete resolution.[146] Further studies are needed to determine the efficacy of infliximab in idiopathic PG.

Etanercept is a recombinant fusion protein of the TNFα receptor bound to the Fc portion of immunoglobulin, binding soluble TNFα. In one study, etanercept resulted in the resolution of 8 of 11 lesions of PG (in seven patients), demonstrating complete healing in a mean of 12.5 weeks.[85] The remaining three ulcers showed a marked reduction in size with no serious adverse effects reported.

Adalimumab is a fully humanized monoclonal antibody that binds both soluble and membrane-bound TNF. One case series of three patients with PG who failed to respond to oral and intravenous corticosteroids, thalidomide, cyclosporine, and mycophenolate mofetil were treated with adalimumab 40 mg once a week with improvement in two of the three patients.[147]

Alefacept, a selective T-cell activation inhibitor blocking CD2:lymphocyte function-associated antigen 3 (LFA3) interactions, has been used in PG with limited success. In one series, four patients were given intramuscular alefacept 15 mg weekly for 20 weeks and then followed up 12 weeks later. One patient cleared completely, two patients showed marked improvement, and one patient had slight improvement.[148]

Efalizumab is a fully humanized recombinant monoclonal antibody that binds to and inhibits the CD11a subunit of LFA1, which mediates leukocyte adhesion and migration. This agent showed initial promise, completely resolving lesions of recalcitrant PG in two cases; however, it was withdrawn from the US and European markets in 2009 due to a concern for increased risk of progressive multifocal leukencephalopathy.[149,150]

Finally, a recent case reported the successful use of ustekinumab, an anti-IL-12/IL-23p40 monoclonal antibody, in a PG lesion leading to complete healing in 14 weeks.[151] Interestingly, the report also found an elevated expression of IL-23A by polymerase chain reaction in the PG lesion compared with normal skin, suggesting a possible mechanism for the efficacy of ustekinumab.

Adverse effects with all biologics include increased risk of infections (and reactivation of tuberculosis), transaminitis, demyelinating disease, a lupus-like syndrome, and a possible increased risk of malignancy. Biologics should be avoided in patients with a history of congestive heart failure, a history of malignancy or risk factors for malignancy (especially lymphoma, melanoma, and chronic obstructive pulmonary disease with a smoking history), and a history of major infection such as tuberculosis.

6.5.6 Other Modes of Immunosuppression

Other immunosuppressive therapies including mycophenolate mofetil, methotrexate, and azathioprine have been used with some success in PG, although are generally considered most effective as adjunctive treatments.[54,103,148,152] Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase, decreasing recruitment and inducing apoptosis of activated T cells.[153] In one series, six of seven patients showed improvement with the addition of mycophenolate mofetil to their regimen. Anemia was reported in one patient in this series.[54] Other common adverse effects include nausea, myelosuppresion, and increased risk of lymphoproliferative disorders. Methotrexate has been shown to decrease neutrophil chemotaxis and found to be effective as an adjunct to cyclophosphamide pulse therapy in one study.[103,152] Azathioprine, a purine analog, acts as an anti-inflammatory agent by impairing DNA synthesis in lymphocytes. Azathioprine has also proven effective in combination with cyclophosphamide in PG.[152] Azathioprine has a slow onset of action (4–6 weeks) and is not appropriate for rapid control of disease. Adverse effects include myelosuppression and gastrointestinal intolerance.

Thalidomide is proposed to be effective in PG based on its inhibition of macrophage phagocytosis and neutrophil chemotaxis. Thalidomide 400 mg/day showed dramatic improvement in one patient with PG and Behcet disease.[154] A second patient, who was unresponsive to methylprednisolone, showed complete healing in 10 weeks on oral thalidomide.[155] Adverse effects include significant teratogenicity, drowsiness, and neuropathy.

Alkylating agents have also been effective in PG; however, the adverse effects associated with these medications including myelosuppression and hemorrhagic cystitis (with cyclophosphamide) generally limits their use to severe, refractory cases.[156,157] In one study, six patients with corticosteroid-unresponsive PG were given oral chlorambucil 2–4 mg/day (two patients were given chlorambucil alone and four patients were given chlorambucil in combination with corticosteroids).[157] Benefits were noted in all six patients within 6 weeks and corticosteroids were eventually discontinued in all patients. Leukopenia was noted in one patient.[157] Pulse cyclophosphamide was demonstrated to induce complete remission in seven of nine patients and partial remission in another patient in one series.[158] Adverse effects included transient hematologic and gastrointestinal toxicity.

According to the literature, 25 patients with PG have been successfully treated with intravenous immunoglobulin (IVIG), with one treatment failure.[159] In all cases the disease was long standing, refractory, severe, and other treatment options were limited. Dosages ranged from 0.5 mg to 1 g/kg/day for 2 days, or 0.4 g/kg/day for 5 days with the number of monthly treatments ranging from 2 to 6.[159,160] Adverse effects of IVIG include headache, nausea, fever, anaphylaxis, and renal failure.

6.6 Emerging Therapeutics

Granulocyte apheresis is a new therapeutic modality for IBD that exerts immunomodulatory effects by selectively removing activated granulocytes and monocytes from peripheral blood. Several case reports have demonstrated efficacy in PG lesions refractory to multiple systemic treatments including cyclosporine.[161,162] Apremilast is an orally active phosphodiesterase-4 inhibitor shown to reduce TNFα production both in vitro and in mouse models for psoriasis and rheumatoid arthritis.[163,164] This promising agent has also recently demonstrated improvement in psoriasis efficacy scores in a single-arm, open-label pilot study, without significant adverse effects,[165] though it has yet to be studied in PG.

7. Outcomes

Long-term results of PG treatment are variable, and outcome data are lacking. Some studies have noted higher rates of recurrence and worse clinical outcomes in systemic disease-associated PG compared with the idiopathic form.[4,166] However, in a series of 42 patients with a median follow-up of 26.5 months, no significant difference in prognosis was seen between patients with idiopathic and disease-associated PG; an overall recurrence rate of 56% was noted.[48] Bennett et al.,[47] in a retrospective case series of 86 patients, observed a mean time to remission with treatment of 11.5 ± 11.1 months in classic PG, versus only 9.0 ± 13.7 months in bullous PG (p = 0.03), with five patients in this cohort whose PG remained refractory to multiple treatments. In a retrospective case series of 21 patients followed for at least 3 years,Mlika et al.[64] reported a 30% rate of complete resolution and a 46% recurrence rate, regardless of whether patients received systemic corticosteroids or clofazimine. More follow-up studies will be needed to establish a consistent understanding of disease outcomes as a function of both disease variants and treatments.

8. Concluding Remarks

Nearly a century after it was first described, PG continues to challenge those seeking to understand, diagnose, and treat this complex disorder. Current research supports an understanding of PG as a systemic inflammatory reaction pattern due to innate immune dysregulation and altered neutrophil chemotaxis. Diagnosis remains difficult in the absence of a disease-specific laboratory or histologic finding; however, recently proposed clinical criteria are useful. Approximately half of all cases are associated with a systemic disease, justifying a thorough search for the most common associated conditions in any patient with a new presentation of PG. There is no gold standard for treatment. The central goals of management are to control inflammation and optimize wound healing. In most cases this will require a combination of wound care, topical agents, and in severe or refractory disease, systemic antimicrobials or immunosuppressants. While historically the first-line systemic agents have been corticosteroids and cyclosporine in severe cases, TNFα inhibitors have recently demonstrated success and will likely play an increasing role in treating this disease in the future. Further clinical trial evidence is needed to better define the short- and long-term efficacy of available and emerging treatments.


  1. 1.

    Brocq L. Nouvelle contribution a l’etude du phagedenisme geometrique. Ann Dermatol Syphil 1916; 6 (1): 1–39

    Google Scholar 

  2. 2.

    Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma (ecthyma) gangrenosum. Arch Dermatol 1930; 22: 655–80

    Google Scholar 

  3. 3.

    Powell FC, Schroeter AL, Su WP, et al. Pyoderma gangrenosum: a review of 86 patients. Q J Med 1985 May; 55 (217): 173–86

    Google Scholar 

  4. 4.

    Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996 Mar; 34 (3): 395–409; quiz 410-412

    Google Scholar 

  5. 5.

    Powell FC, Schroeter AL, Su WP, et al. Pyoderma gangrenosum and sarcoidosis. Arch Dermatol 1984 Jul; 120 (7): 959–60

    Google Scholar 

  6. 6.

    Körber A, Klode J, Al-Benna S, et al. Etiology of chronic leg ulcers in 31,619 patients in Germany analyzed by an expert survey. J Dtsch Dermatol Ges 2011 Feb; 9 (2): 116–21

    PubMed  Google Scholar 

  7. 7.

    Su WPD, Davis MDP, Weenig RH, et al. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol 2004 Nov; 43 (11): 790–800

    Google Scholar 

  8. 8.

    Vidal D, Puig L, Gilaberte M, et al. Review of 26 cases of classical pyoderma gangrenosum: clinical and therapeutic features. J Dermatolog Treat 2004 Jun; 15 (3): 146–52

    Google Scholar 

  9. 9.

    Powell FC, Perry HO. Pyoderma gangrenosum in childhood. Arch Dermatol 1984 Jun; 120 (6): 757–61

    Google Scholar 

  10. 10.

    Miserocchi E, Modorati G, Foster CS, et al. Ocular and extracutaneous involvement in pyoderma gangrenosum. Ophthalmology 2002 Oct; 109 (10): 1941–3

    Google Scholar 

  11. 11.

    Krüger S, Piroth W, Amo Takyi B, et al. Multiple aseptic pulmonary nodules with central necrosis in association with pyoderma gangrenosum. Chest 2001 Mar; 119 (3): 977–8

    Google Scholar 

  12. 12.

    Vignon-Pennamen MD. The extracutaneous involvement in the neutrophilic dermatoses. Clin Dermatol 2000 Jun; 18 (3): 339–47

    Google Scholar 

  13. 13.

    Marie I, Levesque H, Joly P, et al. Neutrophilic myositis as an extracutaneous manifestation of neutrophilic dermatosis. J Am Acad Dermatol 2001 Jan; 44 (1): 137–9

    Google Scholar 

  14. 14.

    Wilson-Jones E, Winkelmann RK. Superficial granulomatous pyoderma: a localized vegetative form of pyoderma gangrenosum. J Am Acad Dermatol 1988 Mar; 18 (3): 511–21

    Google Scholar 

  15. 15.

    Zivanović D, Tanasilović S, Skiljević D, et al. Atypical pyoderma gangrenosum in a patient with osteomyelofibrosis. Vojnosanit Pregl 2007 Nov; 64 (11): 787–9

  16. 16.

    O’Loughlin S, Perry HO. A diffuse pustular eruption associated with ulcerative colitis. Arch Dermatol 1978 Jul; 114 (7): 1061–4

    Google Scholar 

  17. 17.

    Cairns BA, Herbst CA, Sartor BR, et al. Peristomal pyoderma gangrenosum and inflammatory bowel disease. Arch Surg 1994 Jul; 129 (7): 769–72

    Google Scholar 

  18. 18.

    Hughes AP, Jackson JM, Callen JP. Clinical features and treatment of peristomal pyoderma gangrenosum. JAMA 2000 Sep 27; 284 (12): 1546–8

    Google Scholar 

  19. 19.

    Sheldon DG, Sawchuk LL, Kozarek RA, et al. Twenty cases of peristomal pyoderma gangrenosum: diagnostic implications and management. Arch Surg 2000 May; 135 (5): 564–8; discussion 568-9

    Google Scholar 

  20. 20.

    Perry HO, Winkelmann RK. Bullous pyoderma gangrenosum and leukemia. Arch Dermatol 1972 Dec; 106 (6): 901–5

    Google Scholar 

  21. 21.

    Dean SM, Zirwas M. A second case of sunitinib-associated pyoderma gangrenosum. J Clin Aesthet Dermatol 2010 Aug; 3 (8): 34–5

    Google Scholar 

  22. 22.

    Freiman A, Brassard A. Pyoderma gangrenosum associated with isotretinoin therapy. J Am Acad Dermatol 2006 Nov; 55 (5 Suppl.): S107–8

    Google Scholar 

  23. 23.

    ten Freyhaus K, Homey B, Bieber T, et al. Pyoderma gangrenosum: another cutaneous side-effect of sunitinib? Br J Dermatol 2008 Jul; 159 (1): 242–3

    Google Scholar 

  24. 24.

    Tinoco MP, Tamler C, Maciel G, et al. Pyoderma gangrenosum following isotretinoin therapy for acne nodulocystic. Int J Dermatol 2008 Sep; 47 (9): 953–6

    Google Scholar 

  25. 25.

    Rostenberg Jr A. The Shwartzman phenomenon: a review with a consideration of some possible dermatological manifestations. Br J Dermatol 1953 Nov; 65 (11): 389–405

    Google Scholar 

  26. 26.

    Shwartzman G. Concerning the specificity and nature of the phenomenon of local skin reactivity to various bacterial filtrates. J Exp Med 1930 Mar 31; 51 (4): 571–83

    Google Scholar 

  27. 27.

    Vignon-Pennamen MD, Wallach D. Cutaneous manifestations of neutrophilic disease: a study of seven cases. Dermatologica 1991; 183 (4): 255–64

    PubMed  CAS  Google Scholar 

  28. 28.

    Adachi Y, Kindzelskii AL, Cookingham G, et al. Aberrant neutrophil trafficking and metabolic oscillations in severe pyoderma gangrenosum. J Invest Dermatol 1998 Aug; 111 (2): 259–68

    Google Scholar 

  29. 29.

    Parren LJMT, Nellen RGL, van Marion AMW, et al. Penile pyoderma gangrenosum: successful treatment with colchicine. Int J Dermatol 2008 Nov; 47 Suppl. 1: 7–9

    Google Scholar 

  30. 30.

    Brown RE, Lay L, Graham D. Bilateral pyoderma gangrenosum of the hand: treatment with dapsone. J Hand Surg Br 1993 Feb; 18 (1): 119–21

    Google Scholar 

  31. 31.

    Galeazzi M, Gasbarrini G, Ghirardello A, et al. Autoinflammatory syndromes. Clin Exp Rheumatol 2006 Feb; 24 (1 Suppl. 40): S79–85

    Google Scholar 

  32. 32.

    Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol 2009 Sep; 23 (9): 1008–17

    Google Scholar 

  33. 33.

    Weenig RH, Davis MDP, Dahl PR, et al. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med 2002 Oct 31; t347 (18): 1412–8

    Google Scholar 

  34. 34.

    Hsiao JL, Antaya RJ, Berger T, et al. Hidradenitis suppurativa and concomitant pyoderma gangrenosum: a case series and literature review. Arch Dermatol 2010 Nov; 146 (11): 1265–70

    Google Scholar 

  35. 35.

    Braun-Falco M, Kovnerystyy O, Lohse P, et al. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH): a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. Epub 2011 Jul 9

    Google Scholar 

  36. 36.

    al-Rimawi HS, Abuekteish FM, Daoud AS, et al. Familial pyoderma gangrenosum presenting in infancy. Eur J Pediatr 1996 Sep; 155 (9): 759–62

    Google Scholar 

  37. 37.

    Shands JW, Flowers FP, Hill HM, et al. Pyoderma gangrenosum in a kindred: precipitation by surgery or mild physical trauma. J Am Acad Dermatol 1987 May; 16 (5 Pt 1): 931–4

    Google Scholar 

  38. 38.

    Lindor NM, Arsenault TM, Solomon H, et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 1997 Jul; 72 (7): 611–5

    Google Scholar 

  39. 39.

    Yeon HB, Lindor NM, Seidman JG, et al. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet 2000 Apr; 66 (4): 1443–8

    Google Scholar 

  40. 40.

    Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 2002 Apr 15; 11 (8): 961–9

    Google Scholar 

  41. 41.

    Shoham NG, Centola M, Mansfield E, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A 2003 Nov 11; 100 (23): 13501–6

    Google Scholar 

  42. 42.

    Kluin-Nelemans JC, Ramselaar CG. Hepatic abscesses, pyoderma gangrenosum-like dermatitis and IgA immune complexes; a presentation of chronic granulomatous disease in an adult. Neth J Med 1982; 25 (4): 100–4

    PubMed  CAS  Google Scholar 

  43. 43.

    Hinze CH, Lucky AW, Bove KE, et al. Leukocyte adhesion deficiency type 1 presenting with recurrent pyoderma gangrenosum and flaccid scarring. Pediatr Dermatol 2010 Oct; 27 (5): 500–3

    Google Scholar 

  44. 44.

    Coors EA, von den Driesch P. Pyoderma gangrenosum in a patient with autoimmune haemolytic anaemia and complement deficiency. Br J Dermatol 2000 Jul; 143 (1): 154–6

    Google Scholar 

  45. 45.

    Oka M, Berking C, Nesbit M, et al. Interleukin-8 overexpression is present in pyoderma gangrenosum ulcers and leads to ulcer formation in human skin xenografts. Lab Invest 2000 Apr; 80 (4): 595–604

    Google Scholar 

  46. 46.

    Brenner M, Ruzicka T, Plewig G, et al. Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol 2009 Nov; 161 (5): 1199–201

    Google Scholar 

  47. 47.

    Bennett ML, Jackson JM, Jorizzo JL, et al. Pyoderma gangrenosum: a comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore) 2000 Jan; 79 (1): 37–46

    Google Scholar 

  48. 48.

    von den Driesch P. Pyoderma gangrenosum: a report of 44 cases with followup. Br J Dermatol 1997 Dec; 137 (6): 1000–5

    Google Scholar 

  49. 49.

    Bhat RM, Nandakishore B, Sequeira FF, et al. Pyoderma gangrenosum: an Indian perspective. Clin Exp Dermatol 2011 Apr; 36 (3): 242–7

    PubMed  CAS  Google Scholar 

  50. 50.

    Altieri M, Vaziri K, Orkin BA. Topical tacrolimus for parastomal pyoderma gangrenosum: a report of two cases. Ostomy Wound Manage 2010 Sep; 56 (9): 56–9

    Google Scholar 

  51. 51.

    Vavricka SR, Brun L, Ballabeni P, et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol 2011 Jan; 106 (1): 110–9

    Google Scholar 

  52. 52.

    Wasmuth HH, Tranø G, Endreseth BH, et al. Primary sclerosing cholangitis and extraintestinal manifestations in patients with ulcerative colitis and ileal pouch-anal anastomosis. J Gastrointest Surg 2010 Jul; 14 (7): 1099–104

    Google Scholar 

  53. 53.

    Yüksel I, Ataseven H, Başar O, et al. Peripheral arthritis in the course ofinflammatory bowel diseases. Dig Dis Sci 2011 Jan; 56 (1): 183–7

    Google Scholar 

  54. 54.

    Eaton PA, Callen JP. Mycophenolate mofetil as therapy for pyoderma gangrenosum. Arch Dermatol 2009 Jul; 145 (7): 781–5

    Google Scholar 

  55. 55.

    Funayama Y, Kumagai E, Takahashi K-I, et al. Early diagnosis and early corticosteroid administration improves healing of peristomal pyoderma gangrenosumin inflammatory bowel disease. Dis Colon Rectum 2009 Feb; 52 (2): 311–4

    Google Scholar 

  56. 56.

    Moravvej H, Razavi GM, Farshchian M, et al. Cutaneous manifestations in 404 Iranian patients with inflammatory bowel disease: a retrospective study. Indian J Dermatol Venereol Leprol 2008 Dec; 74 (6): 607–10

    Google Scholar 

  57. 57.

    McCallum DI, Kinmont PD. Dermatological manifestations of Crohn’s disease. Br J Dermatol 1968 Jan; 80 (1): 1–8

    Google Scholar 

  58. 58.

    Perry HO. Pyoderma gangrenosum. South Med J 1969 Aug; 62 (8): 899–908

    Google Scholar 

  59. 59.

    Johnson ML, Wilson HT. Skin lesions in ulcerative colitis. Gut 1969 Apr; 10 (4): 255–63

    PubMed  CAS  Google Scholar 

  60. 60.

    Hickman JG, Lazarus GS. Pyoderma gangrenosum: a reappraisal of associated systemic diseases. Br J Dermatol 1980 Feb; 102 (2): 235–7

    Google Scholar 

  61. 61.

    Hong J-B, Su Y-N, Chiu H-C. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome): report of a sporadic case without an identifiable mutation in the CD2BP1 gene. J Am Acad Dermatol 2009 Sep; 61 (3): 533–5

    Google Scholar 

  62. 62.

    Prystowsky JH, Kahn SN, Lazarus GS. Present status of pyoderma gangrenosum: review of 21 cases. Arch Dermatol 1989 Jan; 125 (1): 57–64

    Google Scholar 

  63. 63.

    Tjandra JJ, Hughes LE. Parastomal pyoderma gangrenosum in inflammatory bowel disease. Dis Colon Rectum 1994 Sep; 37 (9): 938–42

    Google Scholar 

  64. 64.

    Mlika RB, Riahi I, Fenniche S, et al. Pyoderma gangrenosum: a report of 21 cases. Int J Dermatol 2002 Feb; 41 (2): 65–8

    Google Scholar 

  65. 65.

    Shankar S, Sterling JC, Rytina E. Pustular pyoderma gangrenosum. Clin Exp Dermatol 2003 Nov; 28 (6): 600–3

    Google Scholar 

  66. 66.

    Hasselmann DO, Bens G, Tilgen W, et al. Pyoderma gangrenosum: clinical presentation and outcome in 18 cases and review of the literature. J Dtsch Dermatol Ges 2007 Jul; 5 (7): 560–4

    Google Scholar 

  67. 67.

    Seitz CS, Berens N, Brücker E-B, et al. Leg ulceration in rheumatoid arthritis: an underreported multicausal complication with considerable morbidity. Analysis of thirty-six patients and review of the literature. Dermatology (Basel) 2010; 220 (3): 268–73

    Google Scholar 

  68. 68.

    English JS, Fenton DA, Barth J, et al. Pyoderma gangrenosum and leucocytoclastic vasculitis in association with rheumatoid arthritis: a report of two cases. Clin Exp Dermatol 1984 May; 9 (3): 270–6

    Google Scholar 

  69. 69.

    Holt PJ, Davies MG, Saunders KC, et al. Pyoderma gangrenosum: clinical and laboratory findings in 15 patients with special reference to polyarthritis. Medicine (Baltimore) 1980 Mar; 59 (2): 114–33

    Google Scholar 

  70. 70.

    Stolman LP, Rosenthal D, Yaworsky R, et al. Pyoderma gangrenosum and rheumatoid arthritis. Arch Dermatol 1975 Aug; 111 (8): 1020–3

    Google Scholar 

  71. 71.

    Duguid CM, O’Loughlin S, Otridge B, et al. Paraneoplastic pyoderma gangrenosum. Australas J Dermatol 1993; 34 (1): 17–22

    PubMed  CAS  Google Scholar 

  72. 72.

    Hay CR, Messenger AG, Cotton DW, et al. Atypical bullous pyoderma gangrenosum associated with myeloid malignancies. J Clin Pathol 1987 Apr; 40 (4): 387–92

    Google Scholar 

  73. 73.

    Jacobs P, Palmer S, Gordon-Smith EC. Pyoderma gangrenosum in myelodysplasia and acute leukaemia. Postgrad Med J 1985 Aug; 61 (718): 689–94

    Google Scholar 

  74. 74.

    Powell FC, Schroeter AL, Su WP, et al. Pyoderma gangrenosum and monoclonal gammopathy. Arch Dermatol 1983 Jun; 119 (6): 468–72

    Google Scholar 

  75. 75.

    Kyle RA. Monoclonal gammopathy of undetermined significance: natural history in 241 cases. Am J Med 1978 May; 64 (5): 814–26

    Google Scholar 

  76. 76.

    Tallon B, Rademaker M, Parkinson G, et al. Cavitary pyoderma gangrenosum treated with local infusion of corticosteroid. J Am Acad Dermatol 2007 Apr; 56 (4): 696–9

    Google Scholar 

  77. 77.

    Masatlioğ lu SP, Göktay F, Mansur AT, et al. Systemic lupus erythematosus presenting as pyoderma gangrenosum in two cases. Rheumatol Int 2009 May; 29 (7): 837–40

    Google Scholar 

  78. 78.

    Kole AK, Ghosh A. Cutaneous manifestations of systemic lupus erythematosus in a tertiary referral center. Indian J Dermatol 2009; 54 (2): 132–6

    PubMed  Google Scholar 

  79. 79.

    Livideanu C, Lipsker D, Paul C, et al. Pyoderma gangrenosum as initial manifestation of Graves’ disease. Clin Exp Dermatol 2006 Sep; 31 (5): 659–61

    Google Scholar 

  80. 80.

    Byrne JP, Hewitt M, Summerly R. Pyoderma gangrenosum associated with active chronic hepatitis: report of two cases. Arch Dermatol 1976 Sep; 112 (9): 1297–301

    Google Scholar 

  81. 81.

    Fonseka HFS, Ekanayake SMB, Dissanayake M. Two percent topical phenytoin sodium solution in treating pyoderma gangrenosum: a cohort study. Int Wound J 2010 Dec; 7 (6): 519–23

    Google Scholar 

  82. 82.

    Paller AS, Sahn EE, Garen PD, et al. Pyoderma gangrenosum in pediatric acquired immunodeficiency syndrome. J Pediatr 1990 Jul; 117 (1 Pt 1): 63–6

    Google Scholar 

  83. 83.

    Farhi D, Cosnes J, Zizi N, et al. Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2402 patients. Medicine (Baltimore) 2008 Sep; 87 (5): 281–93

    Google Scholar 

  84. 84.

    Menachem Y, Gotsman I. Clinical manifestations of pyoderma gangrenosum associated with inflammatory bowel disease. Isr Med Assoc J 2004 Feb; 6 (2): 88–90

    Google Scholar 

  85. 85.

    Charles CA, Leon A, Banta MR, et al. Etanercept for the treatment of refractory pyoderma gangrenosum: a brief series. Int J Dermatol 2007 Oct; 46 (10): 1095–9

    PubMed  Google Scholar 

  86. 86.

    Ayestaray B, Dudrap E, Chartaux E, et al. Necrotizing pyoderma gangrenosum: an unusual differential diagnosis of necrotizing fasciitis. J Plast Reconstr Aesthet Surg 2010 Aug; 63 (8): e655–8

    Google Scholar 

  87. 87.

    Callen JP, Dubin HV, Gehrke CF. Recurrent pyoderma gangrenosum and agnogenic myeloid metaplasia. Arch Dermatol 1977 Nov; 113 (11): 1585–6

    Google Scholar 

  88. 88.

    Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders: atypical forms of pyoderma gangrenosum and Sweet’s syndrome associated with myeloproliferative disorders. J Am Acad Dermatol 1983 Nov; 9 (5): 751–8

    Google Scholar 

  89. 89.

    Stanojevic N, Mai C. It starts with a dog scratch. J Hosp Med 2010 Oct; 5 (8): 494–5

    Google Scholar 

  90. 90.

    Ryu J, Naik H, Yang FC, et al. Pyoderma gangrenosum presenting with leukemoid reaction: a report of 2 cases. Arch Dermatol 2010 May; 146 (5): 568–9

    Google Scholar 

  91. 91.

    Koester G, Tarnower A, Levisohn D, et al. Bullous pyoderma gangrenosum. J Am Acad Dermatol 1993 Nov; 29 (5 Pt 2): 875–8

    Google Scholar 

  92. 92.

    Alibhai SMH, Leach M, Minden MD, et al. Outcomes and quality of care in acute myeloid leukemia over 40 years. Cancer 2009 Jul 1; 115 (13): 2903–11

    Google Scholar 

  93. 93.

    Fox LP, Geyer AS, Husain S, et al. Bullous pyoderma gangrenosum as the presenting sign of fatal acute myelogenous leukemia. Leuk Lymphoma 2006 Jan; 47 (1): 147–50

    Google Scholar 

  94. 94.

    Rafael MR, Fernandes CM, Machado JM, et al. Pyoderma gangrenosum or leukaemia cutis? J Eur Acad Dermatol Venereol 2003 Jul; 17 (4): 449–51

    Google Scholar 

  95. 95.

    Török L, Kirschner A, Gurzó M, et al. Bullous pyoderma gangrenosum as a manifestation of leukemia cutis. Eur J Dermatol 2000 Aug; 10 (6): 463–5

    Google Scholar 

  96. 96.

    Nguyen KH, Miller JJ, Helm KF. Case reports and a review of the literature on ulcers mimicking pyoderma gangrenosum. Int J Dermatol 2003 Feb; 42 (2): 84–94

    Google Scholar 

  97. 97.

    Hemp L, Hall S. Pyoderma gangrenosum: from misdiagnosis to recognition, a personal perspective. J Wound Care 2009 Dec; 18 (12): 521–6

    Google Scholar 

  98. 98.

    Barr KL, Chhatwal HK, Wesson SK, et al. Pyoderma gangrenosum masquerading as necrotizing fasciitis. Am J Otolaryngol 2009 Aug; 30 (4): 273–6

    Google Scholar 

  99. 99.

    Mahajan AL, Ajmal N, Barry J, et al. Could your case of necrotising fascitis be pyoderma gangrenosum? Br J Plast Surg 2005 Apr; 58 (3): 409–12

    Google Scholar 

  100. 100.

    Su WP, Schroeter AL, Perry HO, et al. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol 1986 Oct; 13 (5): 323–30

    Google Scholar 

  101. 101.

    Powell FC, Schroeter AL, Perry HO, et al. Direct immunofluorescence in pyoderma gangrenosum. Br J Dermatol 1983 Mar; 108 (3): 287–93

    Google Scholar 

  102. 102.

    Wenzel J, Gerdsen R, Phillipp-Dormston W, et al. Topical treatment of pyoderma gangraenosum. Dermatology (Basel) 2002; 205 (3): 221–3

    CAS  Google Scholar 

  103. 103.

    Miller J, Yentzer BA, Clark A, et al. Pyoderma gangrenosum: a review and update on new therapies. J Am Acad Dermatol 2010 Apr; 62 (4): 646–54

    Google Scholar 

  104. 104.

    Kean J. The effects of smoking on the wound healing process. J Wound Care 2010 Jan; 19 (1): 5–8

    Google Scholar 

  105. 105.

    Wolf R, Wolf D, Ruocco V. The benefits of smoking in skin diseases. Clin Dermatol 1998 Oct; 16 (5): 641–7

    Google Scholar 

  106. 106.

    Patel GK, Rhodes JR, Evans B, et al. Successful treatment of pyoderma gangrenosum with topical 0.5% nicotine cream. J Dermatolog Treat 2004 Apr; 15 (2): 122–5

    Google Scholar 

  107. 107.

    Fonder MA, Lazarus GS, Cowan DA, et al. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol 2008 Feb; 58 (2): 185–206

    Google Scholar 

  108. 108.

    Gottrup F, Karlsmark T. Leg ulcers: uncommon presentations. Clin Dermatol 2005 Dec; 23 (6): 601–11

    Google Scholar 

  109. 109.

    Siegel DM. Contact sensitivity and recalcitrant wounds. Ostomy Wound Manage 2000 Jan; 46 (1A Suppl.): 65S–74S; quiz 75S-76S

    Google Scholar 

  110. 110.

    Chow RK, Ho VC. Treatment of pyoderma gangrenosum. J Am Acad Dermatol 1996 Jun; 34 (6): 1047–60

    Google Scholar 

  111. 111.

    Ko CB, Walton S, Wyatt EH. Pyoderma gangrenosum: associations revisited. Int J Dermatol 1992 Aug; 31 (8): 574–7

    Google Scholar 

  112. 112.

    Azizan NZ, Gangaram HB, Hussein SH. A novel therapy for the treatment of pyoderma gangrenosum. Med J Malaysia 2008 Mar; 63 (1): 51–4

    Google Scholar 

  113. 113.

    Campbell S, Cripps S, Jewell DP. Therapy insight: pyoderma gangrenosumold disease, new management. Nat Clin Pract Gastroenterol Hepatol 2005 Dec; 2 (12): 587–94

    Google Scholar 

  114. 114.

    Chiba T, Isomura I, Suzuki A, et al. Topical tacrolimus therapy for pyoderma gangrenosum. J Dermatol 2005 Mar; 32 (3): 199–203

    Google Scholar 

  115. 115.

    Le Cleach L, Moguelet P, Perrin P, et al. Is topical monotherapy effective for localized pyoderma gangrenosum? Arch Dermatol 2011 Jan; 147 (1): 101–3

    Google Scholar 

  116. 116.

    Theissen U, Luger TA, Schwarz T. Successful topical administration of cyclosporin A in pyoderma gangraenosum [in German]. Hautarzt 1996 Feb; 47 (2): 132–5

    Google Scholar 

  117. 117.

    Lyon CC, Stapleton M, Smith AJ, et al. Topical tacrolimus in themanagement of peristomal pyoderma gangrenosum. J Dermatolog Treat 2001 Mar; 12 (1): 13–7

    Google Scholar 

  118. 118.

    Ghislain P-D, De Decker I, Lachapelle J-M. Efficacy and systemic absorption of topical tacrolimus used in pyoderma gangrenosum. Br J Dermatol 2004 May; 150 (5): 1052–3

    Google Scholar 

  119. 119.

    Sanders CJ, Hulsmans RF. Successful treatment of pyoderma gangrenosum with topical 5-aminosalicylic acid. Cutis 1993 Apr; 51 (4): 262–4

    Google Scholar 

  120. 120.

    Braun-Falco M, Stock K, Ring J, et al. Topical platelet-derived growth factor accelerates healing of myelodysplastic syndrome-associated pyoderma gangrenosum. Br J Dermatol 2002 Oct; 147 (4): 829–31

    Google Scholar 

  121. 121.

    Tamir A, Landau M, Brenner S. Topical treatment with 1% sodium cromoglycate in pyoderma gangrenosum. Dermatology (Basel) 1996; 192 (3): 252–4

    CAS  Google Scholar 

  122. 122.

    Powell FC, O’Kane M. Management of pyoderma gangrenosum. Dermatol Clin 2002 Apr; 20 (2): 347–55, viii

    Google Scholar 

  123. 123.

    Tsele E, Yu RC, Chu AC. Pyoderma gangrenosum: response to topical nitrogen mustard. Clin Exp Dermatol 1992 Nov; 17 (6): 437–40

    Google Scholar 

  124. 124.

    Moschella SL. Pyoderma gangrenosum: a patient successfully treated with intralesional injections of steroid. Arch Dermatol 1967 Jan; 95 (1): 121–3

    Google Scholar 

  125. 125.

    Goldstein F, Krain R, Thornton JJ. Intralesional steroid therapy of pyoderma gangrenosum. J Clin Gastroenterol 1985 Dec; 7 (6): 499–501

    Google Scholar 

  126. 126.

    Mrowietz U, Christophers E. Clearing of pyoderma gangrenosum by intralesional cyclosporin A. Br J Dermatol 1991 Nov; 125 (5): 499-1

    Google Scholar 

  127. 127.

    Ma G, Jones G, MacKay G. Pyoderma gangrenosum: a great marauder. Ann Plast Surg 2002 May; 48 (5): 546–52; discussion 552-553

    Google Scholar 

  128. 128.

    Classen DA, Thomson C. Free flap coverage of pyoderma gangrenosum leg ulcers. J Cutan Med Surg 2002 Aug; 6 (4): 327–31

    Google Scholar 

  129. 129.

    Límová M, Mauro T. Treatment of pyoderma gangrenosum with cultured keratinocyte autografts. J Dermatol Surg Oncol 1994 Dec; 20 (12): 833–6

    Google Scholar 

  130. 130.

    Niezgoda JA, Cabigas EB, Allen HK, et al. Managing pyoderma gangrenosum: a synergistic approach combining surgical débridement, vacuumassisted closure, and hyperbaric oxygen therapy. Plast Reconstr Surg 2006 Feb; 117 (2): 24e–8e

    Google Scholar 

  131. 131.

    Kaddoura IL, Amm C. A rationale for adjuvant surgical intervention in pyoderma gangrenosum. Ann Plast Surg 2001 Jan; 46 (1): 23–8

    Google Scholar 

  132. 132.

    Long CC, Jessop J, Young M, et al. Minimizing the risk of post-operative pyoderma gangrenosum. Br J Dermatol 1992 Jul; 127 (1): 45–8

    Google Scholar 

  133. 133.

    Rozen SM, Nahabedian MY, Manson PN. Management strategies for pyoderma gangrenosum: case studies and review of literature. Ann Plast Surg 2001 Sep; 47 (3): 310–5

    Google Scholar 

  134. 134.

    Kontochristopoulos GJ, Stavropoulos PG, Gregoriou S, et al. Treatment of pyoderma gangrenosum with low-dose colchicine. Dermatology (Basel) 2004; 209 (3): 233–6

    CAS  Google Scholar 

  135. 135.

    Fukuhara K, Urano Y, Kimura S, et al. Pyoderma gangrenosum with rheumatoid arthritis and pulmonary aseptic abscess responding to treatment with dapsone. Br J Dermatol 1998 Sep; 139 (3): 556–8

    Google Scholar 

  136. 136.

    Galun E, Flugelman MY, Rachmilewitz D. Pyoderma gangrenosum complicating ulcerative colitis: successful treatment with methylprednisolone pulse therapy and dapsone. Am J Gastroenterol 1986 Oct; 81 (10): 988–9

    Google Scholar 

  137. 137.

    Joshi A, Mamta. Behçet’s syndrome with pyoderma-gangrenosum-like lesions treated successfully with dapsone monotherapy. J Dermatol 2004 Oct; 31 (10): 806–10

    Google Scholar 

  138. 138.

    Handler MZ, Hamilton H, Aires D. Treatment of peristomal pyoderma gangrenosum with topical crushed dapsone. J Drugs Dermatol 2011 Sep 1; 10 (9): 1059–61

    Google Scholar 

  139. 139.

    Thiboutot DM, Willmer J, Sharata H, et al. Pharmacokinetics of dapsone gel, 5% for the treatment of acne vulgaris. Clin Pharmacokinet 2007; 46 (8): 697–712

    PubMed  CAS  Google Scholar 

  140. 140.

    Lynch WS, Bergfeld WF. Pyoderma gangrenosum responsive to minocycline hydrochloride. Cutis 1978 Apr; 21 (4): 535–8

    Google Scholar 

  141. 141.

    Gettler S, Rothe M, Grin C, et al. Optimal treatment of pyoderma gangrenosum. Am J Clin Dermatol 2003; 4 (9): 597–608

    PubMed  Google Scholar 

  142. 142.

    Reichrath J, Bens G, Bonowitz A, et al. Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based onmore than 350 patients. J Am Acad Dermatol 2005 Aug; 53 (2): 273–83

    Google Scholar 

  143. 143.

    Elgart G, Stover P, Larson K, et al. Treatment of pyoderma gangrenosum with cyclosporine: results in seven patients. J Am Acad Dermatol 1991 Jan; 24 (1): 83–6

    Google Scholar 

  144. 144.

    Friedman S, Marion JF, Scherl E, et al. Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease. Inflamm Bowel Dis 2001 Feb; 7 (1): 1–7

    Google Scholar 

  145. 145.

    Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J. Am Acad Dermatol 2010 Dec; 63 (6): 949–72; quiz 973-974

    Google Scholar 

  146. 146.

    Brooklyn TN, Dunnill MGS, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut 2006 Apr; 55 (4): 505–9

    Google Scholar 

  147. 147.

    Jacob SE, Weisman RS, Kerdel FA. Pyoderma gangrenosum: rebel without a cure? Int J Dermatol 2008 Feb; 47 (2): 192–4

    Google Scholar 

  148. 148.

    Foss CE, Clark AR, Inabinet R, et al. An open-label pilot study of alefacept for the treatment of pyoderma gangrenosum. J Eur Acad Dermatol Venereol 2008 Aug; 22 (8): 943–9

    Google Scholar 

  149. 149.

    Gulliver W. Successful treatment of recalcitrant pyoderma gangrenosumwith Raptiva. Poster presented at the 16th Congress of the European Academy of Dermatology and Venereology; 2007 May 16; Vienna

    Google Scholar 

  150. 150.

    Woodson J. Use of efalizumab for the successful treatment of chronic recalcitrant pyoderma gangrenosum. Poster presented at the 64th Annual Meeting of the American Academy of Dermatology; 2006 Mar 3-7; San Francisco (CA)

    Google Scholar 

  151. 151.

    Guenova E, Teske A, Fehrenbacher B, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol 2011 Oct; 147 (10): 1203–5

    Google Scholar 

  152. 152.

    Schmidt C, Wittig BM, Moser C, et al. Cyclophosphamide pulse therapy followed by azathioprine or methotrexate induces long-term remission in patients with steroid-refractory Crohn’s disease. Aliment Pharmacol Ther 2006 Jul 15; 24 (2): 343–50

    Google Scholar 

  153. 153.

    Lee MR, Cooper AJ. Mycophenolate mofetil in pyoderma gangrenosum. J Dermatolog Treat 2004 Sep; 15 (5): 303–7

    Google Scholar 

  154. 154.

    Rustin MH, Gilkes JJ, Robinson TW. Pyoderma gangrenosum associated with Behçet’s disease: treatment with thalidomide. J Am Acad Dermatol 1990 Nov; 23 (5 Pt 1): 941–4

    Google Scholar 

  155. 155.

    Federman GL, Federman DG. Recalcitrant pyoderma gangrenosum treated with thalidomide. Mayo Clin Proc 2000 Aug; 75 (8): 842–4

    Google Scholar 

  156. 156.

    Zonana-Nacach A, Jiménez-Balderas FJ, Martínez-Osuna P, et al. Intravenous cyclophosphamide pulses in the treatment of pyoderma gangrenosum associated with rheumatoid arthritis: report of 2 cases and review of the literature. J Rheumatol 1994 Jul; 21 (7): 1352–6

    Google Scholar 

  157. 157.

    Callen JP, Case JD, Sager D. Chlorambucil: an effective corticosteroidsparing therapy for pyoderma gangrenosum. J Am Acad Dermatol 1989 Sep; 21 (3 Pt 1): 515–9

    Google Scholar 

  158. 158.

    Reynoso-von Drateln C, Perla-Navarro AV, Gamez-Nava JI, et al. Intravenous cyclophosphamide pulses in pyoderma gangrenosum: an open trial. J Rheumatol 1997 Apr; 24 (4): 689–93

    Google Scholar 

  159. 159.

    de Zwaan SE, Iland HJ, Damian DL. Treatment of refractory pyoderma gangrenosum with intravenous immunoglobulin. Australas J Dermatol 2009 Feb; 50 (1): 56–9

    Google Scholar 

  160. 160.

    Hagman JH, Carrozzo AM, Campione E, et al. The use of high-dose immunoglobulin in the treatment of pyoderma gangrenosum. J Dermatolog Treat 2001 Mar; 12 (1): 19–22

    Google Scholar 

  161. 161.

    Okuma K, Mitsuishi K, Hasegawa T, et al. A case report of steroid and immunosuppressant-resistant pyoderma gangrenosum successfully treated by granulocytapheresis. Ther Apher Dial 2007 Oct; 11 (5): 387–90

    Google Scholar 

  162. 162.

    Seishima M, Mizutani Y, Shibuya Y, et al. Efficacy of granulocyte and monocyte adsorption apheresis for three cases of refractory pyoderma gangrenosum. Ther Apher Dial 2007 Jun; 11 (3): 177–82

    PubMed  CAS  Google Scholar 

  163. 163.

    Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase- 4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 2010 Feb; 159 (4): 842–55

  164. 164.

    McCann FE, Palfreeman AC, Andrews M, et al. Apremilast, a novel PDE4 inhibitor, inhibits spontaneous production of tumour necrosis factor-alpha from human rheumatoid synovial cells and ameliorates experimental arthritis. Arthritis Res Ther 2010; 12 (3): R107, 1–11

    Google Scholar 

  165. 165.

    Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-armpilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin 2008 May; 24 (5): 1529–38

    Google Scholar 

  166. 166.

    Callen JP, Jackson JM. Pyoderma gangrenosum: an update. Rheum Dis Clin North Am 2007 Nov; 33 (4): 787–802, vi

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Iris Ahronowitz and Joanna Harp contributed equally to this work.

The authors are grateful to Michael Rosenblum, MD, PhD and Lindy P. Fox, MD for providing clinical photographs included in this review. The authors are also grateful to Timothy G. Berger, MD, for his critical review of the manuscript.

No sources of funding were received to prepare this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Correspondence to Dr Kanade Shinkai.

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Ahronowitz, I., Harp, J. & Shinkai, K. Etiology and Management of Pyoderma Gangrenosum. Am J Clin Dermatol 13, 191–211 (2012).

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  • Inflammatory Bowel Disease
  • Crohn Disease
  • Pyoderma Gangrenosum
  • Ustekinumab
  • Hidradenitis Suppurativa