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Violaceous-rimmed ulcers.

A 40-year-old man presented with a violaceous-rimmed ulceration on his inner thigh. He complained of crusting and drainage, but the lesion was otherwise asymptomatic. It began as a pimple, expanded into a small erosion, and then progressed to an ulceration (Figure). Medications at the time of presentation included prednisone and delayed-release mesalamine.

[FIGURE OMITTED]

What is the diagnosis? What are the therapy options?

DIAGNOSIS: Pyoderma gangrenosum (PG) associated with Crohn's disease.

DISCUSSION

PG is an idiopathic neutrophilic dermatosis, which is associated with an underlying systemic disease in over 50% of cases (1, 2) (Table). Clinically, PG begins as follicocentric pustules with inflammatory halos that subsequently expand peripherally and form ulcers with sharply circumscribed violaceous raised edges in which necrotic pustules may be seen (1). Patients may have one or numerous lesions. The incidence of PG is uncertain, but it has been reported as 3 cases per million per year (4). While PG can occur at any age, patients are most commonly women aged 30 to 50 years. Lesions have a predilection for the lower extremities and trunk (5), and PG may occur at sites of trauma, a phenomenon called pathergy (6). Oftentimes, surgical debridement of PG leads to larger lesions and is therefore contraindicated (7). Fever, malaise, myalgias, and arthralgias frequently accompany rapidly progressing lesions (8).

Although the pathogenesis of PG is incompletely understood, the condition appears to be immune mediated (9). Numerous infectious agents have also been implicated in the pathogenesis of PG; however, no specific bacterium, fungus, or virus has been consistently identified (9). The concept of an altered immunologic reactivity is supported by the observation that PG is associated with inflammatory bowel disease, rheumatoid arthritis, non-Hodgkin's lymphoma, and myeloproliferative disorders (10).

Clinical variants of pyoderma gangrenosum

There are four clinical variants of PG: ulcerative, pustular, bullous, and vegetative. The ulcerative form occurs primarily in the extremities or lower trunk (2, 11); however, it has been reported in the vulva, the penis, the breasts, and the head and neck region (12-14). The lower limbs are involved in >70% of patients, and the lesions may arise either by themselves or in response to minor trauma, insect bites, or surgical procedures (11). Pustular PG typically occurs in the setting of ulcerative colitis and presents as painful pustules on the extensor aspects of extremities. Not all pustules evolve into ulcers, and these slowly resolving lesions may persist for unpredictable periods (11). The lesions may progress to, or coexist with, the ulcerative form in patients with inflammatory bowel disease (15-17). Bullous PG is a superficial blistering dermatosis, which may be associated with a concomitant leukemia (18). The lesions consist of bullae a few centimeters in size, resembling bullous impetigo, and often break down rapidly (1). Vegetative PG is a superficial form that generally remains confined to the skin and has no association with systemic disease (19). Lesions typically occur on the trunk and without the violaceous undermining border and pustular base that is characteristic of the ulcerative variant (1).

Evaluation and diagnosis

A thorough history and physical examination are mandatory. A skin biopsy should be sent for routine histologic examination. Additionally, tissue should be sent for special stains and cultures to evaluate for bacterial, fungal, mycobacterial, or viral organisms. To exclude other entities, physicians may order a variety of laboratory tests: complete blood count; chemistry tests (including liver and renal function tests); tests for antinuclear antibodies, antiphospholipid antibodies, and antineutrophil cytoplasmic antibodies; serum protein electrophoresis; immunofixation electrophoresis; and urinalysis. Additionally, chest radiographs and a gastrointestinal tract evaluation are appropriate.

PG is a diagnosis of exclusion based on clinicopathologic correlation. Histologically, lesions are characterized by an accumulation of neutrophils throughout the dermis and epidermis (20). Special stains and cultures for fungal, bacterial, or mycobacterial organisms are all negative (1). Ulcers develop as necrosis of the epidermis ensues after the inflammatory process spreads within the dermis (8). Of note, there is no associated vasculitis.

The clinical differential diagnoses for PG include folliculitis, furuncle, necrotizing vasculitis, cutaneous lymphomas, and insect bites (9). Other conditions to consider are venous, thrombotic, atherosclerotic, vasculitic, or neuropathic ulcers; squamous cell carcinoma; basal cell carcinoma; postoperative gangrene; ecthyma gangrenosum; atypical mycobacterial and clostridial infections; deep mycoses; amebiasis; tropical ulcers; bromoderma; North American blastomycosis and pemphigus vegetans; brown recluse spider bite; and sporotrichosis (9, 21-25).

The histologic differential diagnosis for PG includes Sweet's syndrome, which is another neutrophilic dermatosis without associated vasculitis (10). Clinically, patients with Sweet's syndrome present with symmetrical, red, sharply demarcated papules and plaques associated with fever, malaise, and an elevated peripheral white blood cell count (10, 26).

Treatment and prognosis

Treatment of PG should always start with finding and treating any associated underlying disorder (1). Thereafter, the aim of therapy is to halt the progression of ulcers, promote reepithelialization, minimize pain, and limit scarring. Local (hydrocolloid dressing and intralesional corticosteroids) and systemic therapies may be required for adequate disease control (27-29). Traditionally, the cornerstone of therapy has been treatment with corticosteroids and cyclosporine (30). Sulfa drugs such as dapsone, sulfapyridine, and sulfasalazine have also shown some utility (11). Steroid-refractory cases may require combinations of corticosteroids and cytotoxic drugs such as azathioprine, cyclophosphamide, or chlorambucil (18).

Exciting novel therapeutic options include treatment with infliximab, etanercept, and intravenous immunoglobulin. Several case reports have documented the successful use of infliximab in PG associated with inflammatory bowel disease. Sapienza et al reported rapid resolution of PG in 4 female patients with fistulizing Crohn's disease treated with infliximab (32). Lopez San Roman et al described a patient whose PG could not be controlled with steroids and azathioprine (33). A single dose of infliximab 5 mg/kg was given, and the patient achieved an impressive response of the skin lesions followed by complete healing 3 months later. Additionally, McGowan et al reported a case in which a patient with widespread PG unresponsive to systemic corticosteroids had a rapid clinical remission with etanercept therapy (34).

Several case reports have also described successful use of intravenous immunoglobulin, usually in conjunction with corticosteroids (35, 36). Hagman et al described a patient who was successfully treated with intravenous immunoglobulin 400 mg/kg per day for 5 consecutive days (35). Of note, after 1 week there was an arrest in the evolution of the ulcers and a marked decline in pain, followed by clinical improvement of the ulcers 2 weeks later.

(1.) Crowson AN, Mihm MC Jr, Magro C. Pyoderma gangrenosum: a review. J Cutan Pathol 2003;30:97-107.

(2.) Powell FC, Schroeter AL, Su WP, Perry HO. Pyoderma gangrenosum: a review of 86 patients. Q J Med 1985;55:173-186.

(3.) Wines N, Wines M, Ryman W. Understanding pyoderma gangrenosum: a review. MedGenMed 2001;3(2). Available at http://www.medscape.com/viewarticle/408145.

(4.) Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996;34:395-409.

(5.) Bennett ML, Jackson JM, Jorizzo JL, Fleischer AB Jr, White WL, Callen JP. 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;79:37-46.

(6.) Gudi VS, Julian C, Bowers PW. Pyoderma gangrenosum complicating bilateral mammaplasty. Br J Plast Surg 2000;53:440-441.

(7.) Huish SB, de La Paz EM, Ellis PR III, Stern PJ. Pyoderma gangrenosum of the hand: a case series and review of the literature. J Hand Surg [Am] 2001;26: 679-685.

(8.) Callen JP. Pyoderma gangrenosum. Lancet 1998;351:581-585.

(9.) Ehling A, Karrer S, Klebl F, Schaffler A, Muller-Ladner U. Therapeutic management of pyoderma gangrenosum. Arthritis Rheum 2004;50:3076-3084.

(10.) Lear JT, Atherton MT, Byrne JP. Neutrophilic dermatoses: pyoderma gangrenosum and Sweet's syndrome. Postgrad Med J 1997;73:65-68.

(11.) Powell FC, Collins S. Pyoderma gangrenosum. Clin Dermatol 2000;18: 283-293.

(12.) Lebbe C, Moulonguet-Michau I, Perrin P, Blanc F, Frija J, Civatte J. Steroid-responsive pyoderma gangrenosum with vulvar and pulmonary involvement. J Am Acad Dermatol 1992;27:623-625.

(13.) Farrell AM, Black MM, Bracka A, Bunker CB. Pyoderma gangrenosum of the penis. Br J Dermatol 1998;138:337-340.

(14.) Waterworth AS, Horgan K. Pyoderma gangrenosum--an unusual differential diagnosis for acute infection. Breast 2004;13:250-253.

(15.) O'Loughlin S, Perry HO. A diffuse pustular eruption associated with ulcerative colitis. Arch Dermatol 1978;114:1061-1064.

(16.) Basler RS, Dubin HV. Ulcerative colitis and the skin. Arch Dermatol 1976;112:531-534.

(17.) Shankar S, Sterling JC, Rytina E. Pustular pyoderma gangrenosum. Clin Exp Dermatol 2003;28:600-603.

(18.) Perry HO, Winkelmann RK. Bullous pyoderma gangrenosum and leukemia. Arch Dermatol 1972;106:901-905.

(19.) Peretz E, Cagnano E, Grunwald MH, Hallel-Halevy D, Halevy S. Vegetative pyoderma gangrenosum: an unusual presentation. Int J Dermatol 1999;38: 703-706.

(20.) Callen JP. Neutrophilic dermatoses. Dermatol Clin 2002;20:409-419.

(21.) Carbia SG, Hochman A, Chain M, Dei-Cas I, Lagodin C, Deves A, Woscoff A. Mycosis fungoides presenting with extensive pyoderma gangrenosum-like ulcers. J Eur Acad Dermatol Venereol 2002;16:401-404.

(22.) Ho KK, Browne A, Fitzgibbons J, Carney D, Powell FC. Mycosis fungoides bullosa simulating pyoderma gangrenosum. Br J Dermatol 2000;142: 124-127.

(23.) Kemp DR. Inappropriate diagnosis of necrotizing arachnidism. Watch out Miss Muffet--but don't get paranoid. Med J Aust 1990;152:669-671.

(24.) Sams HH, Hearth SB, Long LL, Wilson DC, Sanders DH, King LE Jr. Nineteen documented cases of Loxosceles reclusa envenomation. J Am Acad Dermatol 2001;44:603-608.

(25.) Byrd DR, El-Azhary RA, Gibson LE, Roberts GD. Sporotrichosis masquerading as pyoderma gangrenosum: case report and review of 19 cases of sporotrichosis. J Eur Acad Dermatol Venereol 2001;15:581-584.

(26.) Sweet R. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964;76: 349-356.

(27.) Chow RK, Ho VC. Treatment of pyoderma gangrenosum. J Am Acad Dermatol 1996;34:1047-1060.

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

(29.) Limova M, Mauro T. Treatment of pyoderma gangrenosum with cultured keratinocyte autografts. J Dermatol Surg Oncol 1994;20:833-836.

(30.) Gettler S, Rothe M, Grin C, Grant-Kels J. Optimal treatment of pyoderma gangrenosum. Am J Clin Dermatol 2003;4:597-608.

(31.) Schofer H, Baur S. Successful treatment of postoperative pyoderma gangrenosum with cyclosporin. J Eur Acad Dermatol Venereol 2002;16:148-151.

(32.) Sapienza MS, Cohen S, Dimarino AJ. Treatment of pyoderma gangrenosum with infliximab in Crohn's disease. Dig Dis Sci 2004;49:1454-1457.

(33.) Lopez San Roman A, Bermejo F, Aldanondo I, Carrera E, Boixeda D, Munoz Zato E. Pyoderma gangrenosum associated with ulcerative colitis: response to infliximab. Rev Esp Enferm Dig 2004;96:420-422.

(34.) McGowan JW IV, Johnson CA, Lynn A. Treatment of pyoderma gangrenosum with etanercept. J Drugs Dermatol 2004;3:441-444.

(35.) Hagman JH, Carrozzo AM, Campione E, Romanelli P, Chimenti S. The use of high-dose immunoglobulin in the treatment of pyoderma gangrenosum. Dermatolog Treat 2001;12:19-22.

(36.) Dobson CM, Parslew RA, Evans S. Superficial granulomatous pyoderma treated with intravenous immunoglobulin. J Am Acad Dermatol 2003;48: 456-460.

From the University of Texas Southwestern Medical School, Dallas, Texas (Berthelot) and the Division of Dermatology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas (Cather).

CINDY BERTHELOT, MS, AND JENNIFER CLAY CATHER, MD

Corresponding author: Jennifer Clay Cather, MD, 5310 Harvest Hill, Suite 260, Dallas, Texas 75230.
Table. Disorders associated with pyoderma gangrenosum*

Category Disorders

Inflammatory Ulcerative colitis
 bowel disease Crohn's disease
 (15%)
Arthritis (37%) Seronegative, monoarticular arthritis,
 affecting large joints
 Symmetrical polyarthritis
 Psoriatic arthritis
Hematologic Acute and chronic myeloid leukemia
 diseases Monoclonal gammopathy in up to 15% of patients
 (usually IgA)
 Large granular lymphocytic leukemia
 Hairy cell leukemia
 Myelofibrosis
 Waldenstrom's macroglobulinemia
 Polycythemia vera
 Hodgkin's, non-Hodgkin's, and cutaneous T-cell
 lymphoma
Humoral immune Congenital and acquired hypogammaglobulinemia
 abnormalities Streaking leukocyte factor
Cell-mediated Defective neutrophil function
 immune Abnormal monocyte function
 abnormalities Congenital deficiency in leukocyte-adherence
 glycoproteins
 Immune deficiency/immunosuppression
Solid tumors Colon, bladder, prostate, breast, bronchus, ovary,
 associated adrenocortical carcinoma
 with PG
Other disorders Chronic active hepatitis, cryoglobulinemia and
 hepatitis C, thyroid disease, chronic obstructive
 pulmonary disease, hidradenitis suppurativa, acne
 conglobata, sarcoidosis, atrophic gastritis,
 diabetes mellitus, lupus erythematosus, Takayasu's
 arteritis, dermatomyositis, HIV, Wegener's
 granulomatosis, sensorineural deafness, paroxysmal
 nocturnal hemoglobinuria, peripheral ulcerative
 keratitis, lung injury, Behcet's disease,
 diverticulitis, regional enteritis

* Based on reference 20; see also references 1 and 2.
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Title Annotation:Dermatology Report
Author:Berthelot, Cindy; Cather, Jennifer Clay
Publication:Baylor University Medical Center Proceedings
Article Type:Clinical report
Geographic Code:1USA
Date:Apr 1, 2005
Words:2030
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