Febrile neutrophilic dermatosis

What is febrile neutrophilic dermatosis?¹

Neutrophilic dermatoses are a group of heterogeneous inflammatory disorders united by a sterile neutrophilic infiltrate on histopathology, often associated with systemic disease.

The cutaneous manifestations of neutrophilic dermatoses are diverse even with several clinical presentations found in the same patient. The location of the neutrophilic infiltrate (epidermal, dermal, and/or subcutaneous), clinical appearance, and disease chronicity help to distinguish each neutrophilic dermatosis. However, neutrophilic dermatoses can occur on a spectrum.

Examples include acute febrile neutrophilic dermatosis (Sweet syndrome), pyoderma gangrenosum, Behçet's disease and neutrophilic eccrine hidradenitis.

Acute febrile neutrophilic dermatosis is characterised by fever and inflamed or blistered skin and mucosal lesions. Acute febrile neutrophilic dermatosis is also called Sweet syndrome, named after Dr Robert Douglas Sweet from Plymouth, England, who first described it in 1964.²

How common is febrile neutrophilic dermatosis? (Epidemiology)¹

Febrile neutrophilic dermatosis is rare. It can occur at any age, but the average age of onset is between 30 and 60 years, with a female predominance.

Aetiology¹

Febrile neutrophilic dermatosis can be grouped into three main subtypes:

• Classic (idiopathic):

  • Associated with infections, vaccinations, inflammatory disorders, and pregnancy.

  • Upper respiratory infections are most commonly cited as an infectious trigger; however, a range of bacterial, viral, and fungal infections have been implicated.

  • Since 2019, febrile neutrophilic dermatosis has been reported following COVID-19 and rarely following vaccination with the Oxford-AstraZeneca, Moderna, and Pfizer-BioNTech vaccines.

  • Inflammatory conditions like inflammatory bowel disease, systemic lupus erythematous (SLE), and other rheumatologic diseases are associated with the development of classic febrile neutrophilic dermatosis.

  • Other states of immune dysregulation have been linked to febrile neutrophilic dermatosis, including HIV and common variable immunodeficiency.

• Malignancy-associated:

  • More commonly reported with haematologic malignancies and myeloproliferative or myelodysplastic disorders compared to solid-organ malignancies. The most common associations are acute myeloid leukaemia, followed by myelodysplastic syndromes.

  • Febrile neutrophilic dermatosis may precede or follow a diagnosis of malignancy. Febrile neutrophilic dermatosis may also signal cancer recurrence.

• Drug-induced:

  • Most commonly associated with colony-stimulating factors, but has also been reported with a variety of medications, non-steroidal anti-inflammatory drugs (NSAIDs).

Febrile neutrophilic dermatosis symptoms (presentation)³

• Acute onset.

• Usually systemically unwell. Moderate to high fever that may occur with the skin lesions or precede them by days or even weeks.

• Other general features may include malaise, arthralgia and headache.

• Lesions are usually multiple and can occur anywhere, but classically the arms, face and neck. Lesions can become widespread, especially if secondary to malignancy.

• The typical lesions are painful, red-purple, tender papules and nodules that coalesce to form plaques, which in some cases take on a targetoid appearance. Lesions can become studded with pustules, and occasionally become bullous. Healing normally occurs without scarring

• Eye manifestations may include conjunctivitis, episcleritis, uveitis and glaucoma.

• Oral ulceration may occur.

Chronic relapsing and remitting febrile neutrophilic dermatosis:

• Fever is variable but polyarthralgia and tiredness are common.

• Urticated pink plaques and papules on trunk and proximal extremities predominate. The face and neck can be involved, especially the mastoid region.

• Lesions vary from completely asymptomatic to intensely itchy.

Neutrophilic dermatosis of the (dorsal) hands:

• This is a rare condition with debate as to whether or not this condition is a localised from of febrile neutrophilic dermatosis.

• Bluish or grey nodules like abscesses appear on the dorsum of the hands. These nodules may ulcerate.

• This is sometimes known as "pustular vasculitis" of the hands, because biopsy shows vasculitis with an infiltration of neutrophil white cells.

Differential diagnosis

• Pyoderma gangrenosum.

• Behçet's disease.

• Erythema nodosum.

• Drug reactions.

Investigations³

• White cell count is elevated with a neutrophil leucocytosis.

• Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) is raised.

• Biopsy if often required for confirmation. Numerous neutrophil inflammatory cells are seen with fragmented neutrophils, called leucocytoclasia, and swelling of the endothelial lining of blood vessels.

• Further investigations will be governed by the potential differential diagnoses and the possible underlying aetiology.

Diagnostic criteria¹

The presence of both major and two minor clinical findings have been proposed as criteria for diagnosis.

Major criteria

• Abrupt onset of tender or painful erythematous plaques or nodules, occasionally with vesicles, pustules, or bullae.

• Predominantly neutrophilic infiltration in the dermis without leucocytoclastic vasculitis.

Minor criteria

• Preceding nonspecific respiratory or gastrointestinal tract infection or vaccination or associated with inflammatory disease, haemoproliferative disorders, solid malignant tumours, or pregnancy.

• Periods of general malaise and fever with body temperature above 38°C.

• Laboratory values during onset showing ESR greater than 20, positive CRP, segmented nuclear neutrophils, bands exceeding 70% in peripheral blood smears, and leucocytosis exceeding 8000/μL. At least three of these four values are necessary.

• Excellent response to treatment with systemic corticosteroids or potassium iodide.

Febrile neutrophilic dermatosis treatment and management¹

Response to treatment is usually very swift, although it will resolve without treatment:

• Urgent referral to dermatology for diagnosis and treatment.

• 4-6 weeks of prednisolone is usually sufficient, but occasionally longer-term low dose treatment is needed.

• For severe or refractory disease, pulse dosed methylprednisolone daily for up to 5 days may be indicated initially.

• Potassium iodide, colchicine and dapsone are common steroid-sparing agents. Other treatment options include colchicine, indomethacin and ciclosporin.

• Tumour necrosis factor alpha (TNF-α) inhibitors are effective and increasingly utilized in IBD-associated SS or rheumatologic-associated febrile neutrophilic dermatosis.

• A multicentre retrospective study of ustekinumab for Crohn disease-associated neutrophilic dermatoses demonstrated remission in 6 out of 7 patients. Treatment with anakinra, an IL-1 receptor antagonist, has also been reported for refractory febrile neutrophilic dermatosis.

• Drug-induced and pregnancy-induced febrile neutrophilic dermatosis can resolve after the corresponding trigger is removed.

• If no underlying cause was found at the initial presentation, it is advisable to re-check a full blood count on an annual basis in view of the possible association with haematological disease.

Prognosis

• With or without treatment there is usually complete resolution without any residual scar.

• There is usually a single episode but up to one-third of patients may develop recurrent episodes, particularly patients who have underlying myelodysplasia or malignancy.³