Residency · Residency · Dermatology

Pyoderma Gangrenosum and Neutrophilic Dermatoses

Introduction

Neutrophilic dermatoses are a spectrum of conditions characterized by dense neutrophilic infiltration of the skin without primary infection. Understanding this group is critical because they frequently masquerade as infections, are associated with systemic diseases, and can be dramatically worsened by surgical intervention (pathergy). The major entities include pyoderma gangrenosum, Sweet syndrome, Behcet disease, and bowel-associated dermatosis-arthritis syndrome.

Pyoderma Gangrenosum (PG)

Epidemiology and Pathogenesis

PG has an incidence of approximately 3 to 10 per million per year, with peak age between 20 and 50 years and a slight female predominance. Pathergy, the characteristic worsening at sites of trauma (surgery, needle sticks, biopsies), is seen in 25 to 50% of cases and is a defining feature of the disease. The pathogenesis involves dysregulated innate immunity with aberrant neutrophil chemotaxis, inflammasome activation (NLRP3), and excessive IL-1beta, IL-8, and TNF-alpha production. The overlap with autoinflammatory syndromes has been increasingly recognized.

Clinical Variants

Classic (Ulcerative) PG

Classic PG begins as a painful pustule or papule that rapidly expands into an ulcer with undermined, violaceous (gun-metal gray) borders. The base is purulent with necrotic tissue, surrounded by erythema and induration. The most common location is the lower extremities (pretibial area). Pain is typically disproportionate to the clinical appearance.

Bullous PG

Bullous PG presents with superficial bullae that erode, resembling a bullous disorder. It is strongly associated with hematologic malignancy, especially AML and MDS, and often affects the face and upper extremities. It may coexist with Sweet syndrome.

Pustular PG

Pustular PG presents with multiple sterile pustules on an erythematous base and is closely associated with inflammatory bowel disease. It overlaps clinically with bowel-associated dermatosis-arthritis syndrome.

Vegetative (Superficial Granulomatous) PG

Vegetative PG is a superficial, non-aggressive variant with verrucous or granulomatous morphology. It is often solitary and limited to the trunk. It is less commonly associated with systemic disease and carries a better prognosis. Histology shows granulomatous inflammation rather than a pure neutrophilic infiltrate.

Peristomal PG

Peristomal PG occurs around colostomy or ileostomy sites due to pathergy from appliance trauma and is frequently associated with IBD.

<image>Clinical photograph series showing the four major variants of pyoderma gangrenosum: classic ulcerative PG with undermined violaceous border on the pretibial area, bullous PG on the upper extremity, pustular PG with sterile pustules, and vegetative/superficial granulomatous PG on the trunk</image>

Associated Conditions

Inflammatory bowel disease (ulcerative colitis more than Crohn disease) is present in 15 to 20% of PG patients. Rheumatologic disease including rheumatoid arthritis and seronegative arthritis is another common association. Hematologic disorders such as MDS, AML, and monoclonal gammopathy (especially IgA) should be evaluated for. PAPA syndrome (pyogenic arthritis, PG, acne) is an autosomal dominant condition caused by PSTPIP1 mutation. PASH syndrome consists of PG, acne, and suppurative hidradenitis. Up to 50% of cases are idiopathic.

Diagnosis

PG is a diagnosis of exclusion with no pathognomonic histology or laboratory finding. Biopsy shows a dense neutrophilic infiltrate in the dermis without vasculitis, and a peripheral biopsy from the undermined border is preferred. Tissue culture to exclude infection is mandatory. The differential diagnosis includes infection (mycobacterial, fungal, bacterial), vascular insufficiency, vasculitis, malignancy (SCC in chronic ulcer), factitial disease, and calciphylaxis. The Su diagnostic criteria (2004) require major criteria (rapid progression of a painful ulcer with irregular undermined border, exclusion of other causes) plus minor criteria (pathergy, systemic disease association, histology consistent with the diagnosis, response to immunosuppression).

Management

Wound care should use non-adherent dressings, and surgical debridement should be avoided due to pathergy risk. For mild or localized disease, superpotent topical corticosteroids (clobetasol), topical tacrolimus 0.1%, and intralesional triamcinolone are appropriate. For moderate to severe disease, systemic corticosteroids (prednisone 0.5 to 1 mg/kg/day) produce a rapid response but have a high relapse rate on taper. Cyclosporine at 3 to 5 mg/kg/day is an effective first-line steroid-sparing agent. Dapsone at 100 to 200 mg/day is useful for mild disease (G6PD must be checked). Mycophenolate mofetil provides steroid-sparing but has slower onset. Among biologics, infliximab has the best evidence and offers rapid onset, with adalimumab and ustekinumab as alternatives. Anakinra (IL-1 receptor antagonist) is rational based on the pathogenesis and has growing evidence. If surgery is unavoidable, perioperative systemic corticosteroids or cyclosporine can reduce pathergy risk.

Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)

Clinical Features

Sweet syndrome presents with abrupt onset of tender, erythematous, edematous plaques and papules that have a pseudovesicular appearance due to intense dermal edema. Systemic symptoms include fever, malaise, and leukocytosis with neutrophilia. Distribution favors the face, neck, and upper extremities in an asymmetric pattern.

Three Clinical Settings

Classical (idiopathic) Sweet syndrome is often preceded by upper respiratory infection, shows female predominance, and may be associated with IBD or pregnancy. Malignancy-associated Sweet syndrome is found in 20% of cases, with AML as the most commonly associated malignancy, along with MDS and lymphoma. Drug-induced Sweet syndrome is most commonly caused by G-CSF, along with all-trans-retinoic acid (ATRA), TMP-SMX, and azathioprine, and resolves with drug discontinuation.

Diagnostic Criteria (modified Su and Liu)

The major criteria are abrupt onset of painful erythematous plaques or nodules and a dense neutrophilic infiltrate on histology without vasculitis. Minor criteria include fever, associated malignancy or IBD, leukocytosis, and excellent response to systemic corticosteroids.

Histopathology

Histology shows a dense diffuse dermal neutrophilic infiltrate with prominent papillary dermal edema. There is no vasculitis, though secondary leukocytoclasia may occur. Absence of significant infection on culture is required.

Management

Systemic corticosteroids (prednisone 0.5 to 1 mg/kg/day) produce a dramatic response within 48 hours. Steroid-sparing options include potassium iodide (SSKI) 300 mg three times daily, dapsone 100 to 200 mg/day, and colchicine. The underlying malignancy should be treated or the offending drug discontinued.

<image>Histopathologic comparison of Sweet syndrome (dense diffuse neutrophilic dermal infiltrate with marked papillary dermal edema and no vasculitis) versus leukocytoclastic vasculitis (perivascular neutrophils with fibrinoid necrosis and red cell extravasation within vessel walls)</image>

Other Neutrophilic Dermatoses

Behcet Disease

Behcet disease is defined by recurrent oral ulcers (required), along with genital ulcers, uveitis, and pathergy (positive pathergy test in approximately 60%). It features neutrophilic vasculitis affecting vessels of all sizes and has a HLA-B51 association. Skin findings include erythema nodosum-like lesions, papulopustular eruption, and pathergy at venipuncture sites. Treatment includes colchicine, dapsone, apremilast (FDA-approved for oral ulcers), azathioprine, and anti-TNF agents for severe disease.

Bowel-Associated Dermatosis-Arthritis Syndrome

This neutrophilic pustular dermatosis is associated with bowel bypass surgery or IBD. It presents with crops of purpuric papules and pustules on the trunk and extremities, fever, and polyarthralgia. The pathogenesis involves immune complex deposition from bacterial overgrowth. Treatment includes antibiotics (metronidazole, tetracyclines) and systemic corticosteroids.

Neutrophilic Eccrine Hidradenitis

Neutrophilic eccrine hidradenitis features a neutrophilic infiltrate surrounding and destroying eccrine glands. It is most commonly associated with chemotherapy (cytarabine and other agents) and is self-limiting, resolving with neutrophil count recovery.

Key Clinical Pearls

PG is a diagnosis of exclusion, and biopsy and culture to exclude infection should always be performed before initiating immunosuppression. Pathergy is the hallmark of PG, meaning unnecessary surgical debridement must be avoided and perioperative immunosuppression should be considered if surgery is unavoidable. Bullous PG should prompt evaluation for hematologic malignancy, particularly AML and MDS. Sweet syndrome with atypical or bullous features in an older patient warrants thorough evaluation for underlying malignancy. Infliximab has the strongest evidence among biologics for refractory pyoderma gangrenosum.

References

1. Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol. 2009;23(9):1008-1017.
2. George C, Deroide F, Biber M. Pyoderma gangrenosum — a guide to diagnosis and management. Clin Med (Lond). 2019;19(3):224-228.
3. Cohen PR. Sweet syndrome — a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34.
4. Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55(4):505-509.

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