Acute Febrile Neutrophilic Dermatosis

Acute febrile neutrophilic dermatosis may occur with various disorders (see table Disorders and Medications Associated with Acute Febrile Neutrophilic Dermatosis). It is often classified into 3 categories:

• Classical (idiopathic)

• Cancer-associated

• Drug-induced

Sweet syndrome-like dermatosis in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is another important category. VEXAS is caused by an acquired (somatic) mutation in the UBA1 gene that produces a true neutrophilic dermatosis driven by clonal infiltration of genetically abnormal inflammatory cells into the skin rather than by reactive or paraneoplastic mechanisms, and should be suspected in older males with relapsing Sweet syndrome, cytopenias, or macrocytosis.

Approximately 20% of patients have an underlying cancer (1), many of which are hematologic cancers, especially myelodysplastic syndromes and acute myelogenous leukemia. The dermatosis often precedes the cancer diagnosis.

Classical acute febrile neutrophilic dermatosis affects mostly women ages 30 to 60. In contrast, men who develop the condition are usually older (1). It can occur in children in approximately 5 to 8% of cases (2).

The exact pathogenesis of acute febrile neutrophilic dermatosis is incompletely understood; however, proinflammatory cytokines, including interleukin (IL)-1, IL-17, and interferon-gamma, are predominant and may play a role in lesion formation (3).

Patients are febrile and have painful, tender, and edematous erythematous to violet nodules or papules, most often on the face, neck, and upper extremities, especially the dorsum of the hands. The lesions may have a pseudovesicular appearance due to papillary dermal edema. Papules and nodules may coalesce to form plaques. Oral lesions can also occur. Pathergy may also occur, with lesions developing at sites of mild trauma. The lesions often develop in crops and may appear annular. Each crop is usually preceded by fever and persists for days to weeks. Rarely, bullous and pustular lesions are present as well.

Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome) (1)

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This photo shows erythematous papules and plaques on the dorsum of the hand of a person with acute febrile neutrophilic dermatosis (Sweet syndrome). Some of the papules are annular and some are pseudovesiculated.

PDC/SCIENCE PHOTO LIBRARY

Less common variants include a bullous form that can ulcerate and resemble pyoderma gangrenosum and a subcutaneous form involving the subcutaneous fat that typically has 2- to 3-cm erythematous nodules, commonly affecting the extremities. When on the lower extremities, this form can resemble erythema nodosum.

Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome) (2)

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This photo shows tender, erythematous, well-demarcated papules and plaques that are characteristic of acute febrile neutrophilic dermatosis (Sweet syndrome).

BIOPHOTO ASSOCIATES/SCIENCE PHOTO LIBRARY

Extracutaneous manifestations are rare and can involve the eyes (eg, conjunctivitis, episcleritis, iridocyclitis), joints (eg, arthralgia, myalgia, arthritis), and internal organs (eg, neutrophilic alveolitis; sterile osteomyelitis; psychiatric or neurologic changes; transient kidney, liver, and pancreatic insufficiency).

• History and physical examination

• Skin biopsy

The diagnosis of acute febrile neutrophilic dermatosis is suggested by the abrupt appearance of painful, tender, erythematous plaques or nodules and by histopathologic findings of neutrophilic dermal infiltrates. The diagnosis is established based on both major criteria, described above, plus at least 2 minor criteria: fever > 38° C; the presence of an associated underlying inflammatory, infectious or neoplastic condition or implicated medication; excellent response to systemic glucocorticoids or potassium iodide; and abnormal laboratory findings, including an elevated erythrocyte sedimentation rate, positive C-reactive protein, leukocytosis, or neutrophilia. Differential diagnoses can include erythema multiforme, erythema elevatum diutinum, subacute cutaneous lupus erythematosus, pyoderma gangrenosum, and erythema nodosum.

The histopathologic pattern is that of edema in the upper dermis with a dense infiltrate of neutrophils in the dermis. Vasculitis may be present but is secondary.

A complete blood count (CBC) should also be performed, which may show neutrophilia. If the CBC is abnormal, a bone marrow biopsy should be considered to diagnose an underlying hematologic disorder.

In older males with relapsing neutrophilic dermatosis, particularly with associated macrocytic anemia, thrombocytopenia, or elevated acute phase reactants, VEXAS syndrome should be considered, and the UBA1 gene sequencing of peripheral blood or bone marrow should be performed to confirm the diagnosis.

• Systemic glucocorticoids

• Treatment of underlying cause (when applicable)

The treatment of acute febrile neutrophilic dermatosis involves systemic glucocorticoids (1). For example, prednisone 0.5 to 1.5 mg/kg orally once a day tapered over 3 weeks may be used. When an underlying cause is identified, it should be addressed concurrently such as treating an associated malignancy or withdrawing the offending drug in drug-induced cases.

Colchicine 0.5 mg orally 3 times a day or potassium iodide 300 mg orally 3 times a day are alternative treatments. Antipyretics are also recommended.

For cases that are challenging to treat or do not respond to initial therapy, oral dapsone, indomethacin, clofazimine, or cyclosporine can be given.

Other treatments used for refractory disease include biologics (eg, anakinra, infliximab, etanercept), thalidomide, minocycline, and mycophenolate mofetil.

For localized involvement, topical high-potency or intralesional glucocorticoids (eg, triamcinolone acetonide) may help.