Post-traumatic Pyoderma Gangrenosum
Abstract: Chronically nonhealing wounds caused by pyoderma gangrenosum (PG) are rare and often misdiagnosed. Since PG has no pathognomonic features, the diagnosis is based on clinical grounds. It is a diagnosis of exclusion and presents a considerable challenge, particularly in the absence of systemic diseases commonly associated with PG. Mistreatment or delayed proper treatment can be harmful to patients. The need to recognize trauma (pathergy) as a potential trigger of PG is important for the optimal management of these wounds. The authors present 5 patients who had PG following different forms of trauma at or near the wound site.
Address correspondence to: Philip W. Paparone, DO Stockton Medical Complex 72 West Jimmie Leeds Road Absecon, NJ 08205-9407 Phone: 609-652-2240 Fax: 609-748-1029 E-mail: email@example.com
Pyoderma gangrenosum (PG) is a rare gangrene of the skin, characterized by rapidly progressive, painful ulceration with violaceous, undermined borders.1–3 Lesions often begin with a discrete pustule with surrounding erythema that quickly breaks down to form the characteristic ulceration. The legs are most commonly affected, but other parts of the skin and mucous membranes might also be involved.1 In many cases, PG is associated with systemic disease—most commonly inflammatory bowel disease, arthritis, hepatitis, and myeloproliferative disorders.4,5 Additionally, PG is often associated with trauma in patients who may or may not have systemic disease as a consequence of pathergy—the process in which the induction of a lesion at a site of minor trauma occurs.4 While the diagnosis of PG is based on exclusion, the etiology of PG remains unknown. Histopathologic features are not diagnostic; however, biopsy is useful for the exclusion of other diseases. As a neutrophilic dermatosis, PG often is characterized by the presence of marked neutrophilic infiltrates in the dermis. Misdiagnosis is not uncommon (as high as 10%),6 and can result in inappropriate and potentially detrimental treatment. The proper treatment of PG, often as much of a challenge as its diagnosis, usually requires systemic corticosteroids or other immunosuppressive medications.5 The present report describes 5 cases of post-traumatic PG, and demonstrates the need for appreciating the significance of trauma (pathergy) in the evaluation of chronically nonhealing wounds. It is proposed that increased recognition of associated trauma in PG, as well as suspected trauma, may decrease the incidence of costly misdiagnosis.
Patient 1. A 58-year-old man presented with a wound on the right lower leg. It was associated with a traumatic injury that had occurred on a boat. The wound improved slowly with local wound care. Vascular problems were suspected and later confirmed. Cultures grew a Hormonema fungus that was treated, but this treatment did not produce significant wound improvement. Pyoderma gangrenosum was suspected and a biopsy was performed. Results of the biopsy were consistent with PG. The patient was placed on thalidomide (100 mg twice daily) and prednisone (60 mg once daily). Consequently, the wound healed over the course of several months. The patient responded well and the wound remained healed until he accidentally dropped a stapler on his right leg, which caused a new wound (Figure 1). Treatment with thalidomide (100 mg once daily) and prednisone (60 mg once daily) was effective. When the wound showed signs of improvement, the prednisone was tapered off gradually over 2 months. The wound finally healed and the thalidomide treatment was stopped. Patient 2. An 86-year-old woman with Alzheimer’s disease presented with a nonhealing wound of 3–4 weeks’ duration, 3 cm–4 cm above the right medial malleolus. The patient was unable to provide adequate medical history because of memory loss. Trauma was suspected because of signs of bruising above the wound (Figure 2). Almost 95% of the wound was covered with yellow slough tissue. The patient described a throbbing pain. She was treated with cefadroxil (500 mg twice daily) and had minimal improvement. A specimen for wound culture was taken. Some granulation tissue had developed in the wound, but the throbbing pain persisted. A violaceous border appeared around the wound. Pus and sinus tracts appeared in another location. The wound culture produced no growth. As soon as PG was identified prednisone (10 mg once daily) was administered. The patient’s Alzheimer’s disease and memory loss hampered compliance, resulting in missed days of treatment and the wound became larger. The dosage of prednisone was gradually doubled (20 mg once daily) and methotrexate (5 mg once weekly) was added. The patient responded well to the new regimen. Methotrexate was stopped because of compliance problems. The patient continued taking prednisone. Since the wound responded to prednisone, no biopsy was ordered. As the wound healed, prednisone was gradually tapered. Patient 3. A 40-year-old woman presented with a history of trauma (ie, tibial fracture) and a nonhealing wound of the left leg complicated by cellulitis (Figure 3). Cellulitis was treated with antibiotics and was resolved. The wound developed a violaceous border and multiple sinus tracts. A biopsy was taken and the results were consistent with PG. The patient was placed on prednisone (60 mg once daily). Dramatic improvement was noted over a course of 2 weeks. However, PG reappeared after subsequent gradual tapering of treatment. Prednisone was reintroduced at 80 mg daily until healing, intact skin was evident. The medication was gradually tapered after it was observed that the wound healed. The patient returned for successful repeat treatment of a similar wound at the same site. Patient 4. A 90-year-old woman presented with an open wound and cellulitis of the right lower leg (Figure 4). Stasis dermatitis, hourglass deformity, edema, and venous insufficiency were involved. Ten days prior, the patient had suffered a traumatic injury to the lower right leg from a wheelchair accident. She had 2 courses of cephalexin (500 mg, 3 times daily) and ciprofloxacin (500 mg, twice daily) prior to her office visit. No healing had occurred in the time that had passed. The wound was mechanically debrided, and redressed with Vaseline™ gauze (Covidien, Mansfield, Mass), Soft Kling® Flexible Dressing (Johnson and Johnson, Somerville, NJ), and Tubigrip™ (ConvaTec, Princeton, NJ). The patient was started on clindamycin (300 mg 3 times daily) to address possible methicillin-resistant Staphylococcus aureus (MRSA). Wound cultures showed presence of MRSA and Pseudmonas. The erythema, associated pain, and swelling all improved after clindamycin adminstration. The wound slowly improved over 2 months. Pustules then developed and the skin proximal to the main wound deteriorated. Characteristic signs of PG appeared including sinus tracts, pustules, and purulent drainage. Cultures were negative at this time. Biopsy was deferred due to the patient’s advanced age. The patient was started on a low dose of prednisone (10 mg once daily) because of her advanced age and the medication’s possible side effects. Slight improvement occurred, and the dose of prednisone was raised to 15 mg daily, and eventually to 20 mg daily. The wound healed over the course of 2 months, after which the prednisone was tapered off. Patient 5. A 68-year-old woman presented with a wound on the left shin following trauma to the leg from striking a car door that had occurred 5 months earlier, as well as a second wound beside it, which had subsequently evolved (Figure 5). She had seen 3 physicians previously for treatment. She had been directed to use Epsom salts, was diagnosed with lymphedema, treated with compression wraps, underwent sharp debridement with general anesthesia, and was placed on negative pressure wound therapy (V.A.C.® Therapy™, KCI, San Antonio, Tex) for 2 months with no signs of improvement. At this point, she sought treatment from the authors. She had a history of left ankle fusion, fractured left patella, and bilateral knee replacements. Radiographs were negative for osteomyelitis. Use of an Unna boot helped slightly, but on day 7, two pustules proximal to the wounds were seen. On day 14, a purple wound border was noted. The patient was then started on prednisone (20 mg once daily). Seven weeks later, following recreational travel, she returned to the authors’ clinic, by which time the pustules had healed and the wound bed had improved. Methotrexate (5 mg once weekly) was added to the treatment regimen. Subsequently, over the course of 6 weeks, progressive healing of both wounds was observed. Prednisone and methotrexate were successfully tapered. Cribriform scarring was noted.
Pyoderma gangrenosum (PG) is reported to be the cause in approximately 12% of cases of chronically nonhealing wound.7 First described in 1930,8 PG is a chronic, painful, debilitating ulceration of the skin. Streptococci and staphylococci were originally implicated as causes because of the inflammatory and purulent nature of the condition. Presently, however, the etiology of PG remains unknown. The current belief is that bacteria most likely do not directly cause PG nor that PG is infectious in nature.5 Many conditions can produce skin ulcers that clinically resemble PG including venous ulceration, cutaneous infections, vascultitis, and malignancy, which are misdiagnosed as PG prior to a definitive diagnosis.6 Therefore, a thorough evaluation that includes biopsy is required in cases of suspected PG in order to rule out the diagnoses of ulcerations that mimic PG. In the authors’ experience, the recognition of different forms of trauma with pathergistic potential in the development of PG is useful in this evaluation. Pyoderma gangrenosum frequently occurs in patients with systemic disease. Common associations include inflammatory bowel disease (eg, chronic ulcerative colitis, regional enteritis, granulomatous colitis), arthritis (eg, seronegative with or without inflammatory bowel disease, rheumatoid arthritis, spondylitis, osteoarthritis), and hematologic diseases (myelocytic leukemias, hairy cell leukemia, myelofibrosis, agnogenic myeloid metaplasia, monoclonal gammopathy).1 Rare associations include chronic active hepatitis, myeloma, polycythemia rubra vera, thyroid disease, and diabetes mellitus, among others.1,3–5 At the same time, in 40% to 50% of cases, PG occurs in patients with no known associated systemic disease, and its occurrence is assumed to be sporadic.9–13 Almost 40% of PG cases follow minor trauma.4,14 Systemic disease may or may not be involved with trauma-induced PG. Finkel and Janowitz15 described 5 patients with inflammatory bowel disease (ie, ulcerative colitis and Crohn’s disease) and PG in whom antecedent trauma was a common precipitating factor. In 4 of these patients, there was no association with clinical exacerbation of disease activity. The trauma in all 5 patients occurred on a lower extremity where PG subsequently developed; in 1 patient, it also developed on the hand in addition to the original injury site. Of the 5 patients with post-traumatic PG described in the present report, no patient had PG associated with systemic disease. Holbrook et al14 described a case of post-traumatic PG involving a dog bite to the medial aspect of the left leg. Previous medical history revealed a weakly seropositive polyarthritis for the previous 2 years, but at the time she presented with the PG ulcer, 2 weeks after the trauma, the patient’s arthritis was quiescent. The ulcer was 5 cm and had a green, sloughy base and bluish edge, surrounding erythema, and had an offensive odor. Misdiagnosis of the PG as an infected ulcer secondary to a dog bite resulted in intravenous (IV) antibiotic therapy and subsequent skin grafting, which later became erythematous and broke down, necessitating readmission to the hospital 2 months post-surgery. A full blood count was then taken and showed mild anemia with severe leukopenia, lymphopenia, and neutropenia. The patient was referred to the clinical immunology unit where a provisional diagnosis of PG was made. Corticosteroid therapy led to improvement in her inflammatory markers and the wound healed completely in 6 months. Callen and Jackson1 reported pathergy as a common feature of both “classic” and atypical forms of PG in which ulcers characterize the classic form, and deep erosions with bullous blue-gray margins characterize the atypical form. They observed that misdiagnosed PG wounds treated erroneously for infection are often worsened by debridement, as a consequence of the pathergy phenomenon. They advise that in the evaluation of possible PG, the use of biopsy to exclude other diseases should not be deferred because of concerns of potentially extending lesions through pathergy. The neutrophil is the principle cell in PG pathology.5 Pyoderma gangrenosum is deemed a neutrophilic dermatosis and belongs to a continuous spectrum encompassing 4 other entities: subcorneal pustular dermatosis, Sweet’s syndrome, erythema elevatum diutinum, and neutrophilic eccrine hidradenitis.12 These neutrophilic dermatoses inflammatory disorders share a common tendency for pathergy—the induction of the inflammatory process after skin trauma. The role of pathergy in the development of PG suggests altered, exaggerated, and uncontrolled inflammatory responses to nonspecific stimuli. As a consequence of pathergy, a wide range of minor trauma may induce new PG lesions, including accidental bumps, skin scrapes, insect bites, biopsies, intradermal skin testing or injections, and surgical incisions.5,17 A rare case of pathergy-induced PG, involving more severe trauma, has been described in a battered child—the first case of PG reported that was precipitated after physical assault.18 Systematic studies of the pathergy reaction in PG have yet to be reported. However, pathergy studies of Behçet’s disease, which like PG, is a neutrophilic dermatosis, have been performed. Gül et al19 reported on the immunohistology of skin pathergy reaction in Behçet’s disease. The authors found subcorneal pustule formation and a variable, dense, mononuclear infiltrate of T lymphocytes and monocytes around vessels and skin appendages that extended into the deep dermis. Endothelial cells expressed E-selectin and ICAM-1, but not vascular cell adhesion molecule-1 (VCAM-1). The authors suggested that the pathergy reaction might result from an antigen-independent, delayed-type, hypersensitivity-like reaction. It has been suggested that this reaction would differ from the normal response to trauma by a disproportionate release of inflammatory cytokines from injured keratinocytes, which infiltrating activated lymphocytes might later amplify.4 Studies of pathergy in PG are needed to more fully understand its role in the pathogenesis of this disease. Recognizing the significance of trauma in the diagnosis of PG, the authors sought for history of it in the evaluation of all patients described here. Four of the 5 patients had a history of lower leg trauma. The Alzheimer’s disease and memory loss of patient 2 prevented her from providing a definitive history of trauma. Trauma was suspected because of the bruising near the site on the lower leg where the PG wound occurred. Although this patient could not remember a specific incident, she did describe “bumping into things” and agreed that trauma was possible. In another patient (patient 1), PG recurred as a consequence of accidental repeat injury to the same leg that had been successfully treated and healed. Patients with PG often present with a longstanding wound that has not healed with various medical therapies and/or surgical therapy, the latter of which possibly exacerbates the wound due to pathergy. Ruling out peripheral vascular arterial disease and chronic venous insufficiency need to be addressed. When PG wounds have been present for a significant amount of time, multiple therapies tend to alter the appearance of the disease, so that it cannot be diagnosed initially. However, with conservative wound care management, the typical characteristics of PG will eventually emerge. In the management of some patients, a surgical service initially evaluates the wound and considers it an abscess, which leads to wound debridement. This is what happened in the case of patient 3. Patient 3 had a lower extremity tibial fracture to which a cast was applied. When the cast was removed, what was thought to be an abscess was debrided. Subsequently, another cast was applied to the fracture and the opportunity to track the wound and inspect it was not possible. When the second cast was removed, it was found that the wound had not healed. The patient then was referred to the authors’ clinic. The typical signs of PG eventually appeared, and the correct diagnosis was made. The authors’ experience illustrates that PG presents a diagnostic challenge. The risk of overdiagnosis or underdiagnosis must be appreciated.6,20–23 Diagnosis of PG should be considered in patients with nonhealing wounds and purulent ulcers that affect the legs or peristomal sites. To confirm the diagnosis, specific features should be sought, including pathergy, crater-like holes or cribriform scarring, and systemic disease associated with PG (eg, inflammatory bowel disease).21 Other causes of ulceration must be excluded. In the treatment of PG, the injection of glucocorticoids into the lesions as first-line therapy is not recommended1 because of the risk of exacerbating the lesions through pathergy. When targeted, tumor necrosis factor inhibition is warranted in the treatment of PG;2 infliximab is the recommended drug because etanercept and adalimumab are administered subcutaneously and, therefore, pose a risk of pathergy.1 In the local care of PG wounds, moist dressings (ie, Vaseline gauze) should be used to prevent trauma to the underlying tissue on removal and possible pathergy. Aggressive wound debridement or skin grafting should be avoided to prevent pathergy, but when either form of care is necessary, concomitant systemic therapy is required to halt the inflammatory process.
Pyoderma gangrenosum is a rare, poorly understood, noninfectious, neutrophilic, ulcerating skin disease. The cases of post-traumatic PG described in the present report demonstrate the importance of considering the diagnosis of PG in an ulcer when there is a history of minor trauma (pathergy) without associated systemic disease. Minor trauma preceding the development of an ulcer is an important piece of historical data to obtain in managing patients with suspected PG. Treatment involving intralesional glucocorticoid injection, aggressive debridement, or skin grafting should be used with caution due to the risk of pathergy that can exacerbate PG wounds. From the Wound Care Clinic of South Jersey, Galloway, New Jersey