Acute febrile neutrophilic dermatosis
What is acute febrile neutrophilic dermatosis?
Acute febrile neutrophilic dermatosis is an uncommon skin condition characterised by fever and inflamed or blistered skin and mucosal lesions. Neutrophilic dermatoses are autoinflammatory conditions often associated with systemic disease.
Acute febrile neutrophilic dermatosis also has the eponymous name, Sweet syndrome or disease—named after Dr Robert Douglas Sweet from Plymouth, England, who first described it in 1964.
Who gets acute febrile neutrophilic dermatosis?
Acute febrile neutrophilic dermatosis most often occurs in middle-aged women, but men, children (rarely) and the elderly may also be affected. It has been found to be more common in individuals carrying the genetic marker HLA B54.
Acute febrile neutrophilic dermatosis may affect previously healthy individuals, but often arises in the context of an acute systemic infection or an underlying chronic condition.
What causes acute febrile neutrophilic dermatosis?
The exact cause of acute febrile neutrophilic dermatosis is unknown. Pro-inflammatory cytokines interleukin-1 and tumour necrosis factor alpha (TNFα) play a role.
Acute febrile neutrophilic dermatosis may follow:
- Sun exposure
- Upper respiratory tract infection (eg chest infection, streptococcal throat infection)
- Inflammatory bowel disease (eg ulcerative colitis or Crohn disease)
- Rheumatoid arthritis , lupus erythematosus and relapsing polychondritis
- Blood disorders including leukaemia (most often acute myelogenous leukaemia or myelodysplastic syndromes). These may cause histiocytoid Sweet syndrome (see above).
- Internal cancer usually of bowel, genitourinary organ or breast
- Gastrointestinal infection (eg campylobacter)
- Drugs, including azathioprine, granulocyte colony stimulating factor (G-CSF), nonsteroidal anti-inflammatory medications, cotrimoxazole and other antibiotics, TNFα inhibitors, carbamazepine and several others
In many people with acute febrile neutrophilic dermatosis, no underlying condition is found.
What are the symptoms of acute febrile neutrophilic dermatosis?
Acute febrile neutrophilic dermatosis may occur once or recur on several occasions. It is characterised by some or all of the following symptoms:
- High or moderate fever
- Tiredness and malaise (feeling unwell)
- Skin lesions
- Sore eyes and/or mouth ulcers
- Aching joints
- Sometimes other organs are affected, including bones, nervous system, kidneys, intestines, liver, heart, lungs, muscles and spleen.
What do the skin lesions look like?
Skin lesions of acute febrile neutrophilic dermatosis may be few in number or numerous. They are characteristically tender and may be extremely painful. They persist for days to weeks. The limbs and neck are the most commonly affected sites, but other areas of skin and mucosa may be involved. In some patients, they arise only in sun-exposed areas. Sweet syndrome lesions may have a range of appearances.
- Small papules (bumps) or vesicles (blisters)
- Larger thickened or swollen plaques (flat patches) or nodules (lumps)
- Pseudovesicular appearance (almost blistered)
- Annular (ring-shaped) lesions
- Erosions and ulcers resembling atypical pyoderma gangrenosum
Acute febrile neutrophilic dermatosis often causes erosions or ulcers inside the mouth, on the tongue or on the lips.
Ocular acute febrile neutrophilic dermatosis presents as a sore, red, sticky eye. It can lead to ulceration and loss of vision due to conjunctivitis, dacryoadenitis, keratitis, episleritis, scleritis, iritis, uveitis, glaucoma and choroiditis.
Subcutaneous acute febrile neutrophilic dermatosis
Subcutaneous neutrophilic dermatosis is a form of panniculitis. It is also called subcutaneous Sweet syndrome.
- It is characterised by deep, painful nodules and plaques.
- Skin lesions may ulcerate and discharge oily material.
- These may develop on any area of skin.
- Systemic symptoms include fever, malaise, and joint pains.
- There is an association with myeloid dysplastic syndromes.
- Biopsy shows lobular infiltration of neutrophils in the subcutaneous fat without vasculitis.
There is debate whether neutrophilic panniculitis without neutrophilic involvement of the dermis should be separately classified.
Neutrophilic dermatosis of hands
Neutrophilic dermatosis of the hands is considered a localised variant in which there are purplish nodules on the backs of the thumb, fingers and hand, or less often, on palmar surfaces.
Histiocytoid Sweet syndrome was first described in 2005. In this form of acute febrile neutrophilic dermatosis, instead of neutrophils, inflammation is associated with immature myeloid cell infiltration on biopsy. The name arises from the similar appearance of these monocytic cells to histiocytes. It can difficult to distinguish from leukaemia cutis.
The skin lesions in histiocytoid Sweet syndrome typically include multiple red, purplish or brownish oval shaped patches, plaques and nodules. The rash may be persistent but may improve with successful treatment of the underlying disease or withdrawal of causative medication.
Histiocytoid Sweet syndrome has been reported in:
- Myelodysplastic syndrome
- Myeloproliferative disorders including leukaemia
- Bortezomib-treated multiple myeloma
- Lymphocyte-predominant Hodgkin lymphoma
- Rheumatoid arthritis
How is acute febrile neutrophilic dermatosis diagnosed?
Acute febrile neutrophilic dermatosis may be diagnosed clinically, but at times it may be difficult to distinguish from infections such as chickenpox, or inflammatory conditions such as vasculitis. The diagnosis is usually confirmed on skin biopsy. Special stains may be necessary.
Diagnostic criteria for classic acute febrile neutrophilic dermatosis have been proposed.
- Abrupt onset of tender or painful red or purplish plaques or nodules
- Biopsy shows inflammation that is composed mainly of neutrophils without vasculitis
- Preceding fever or infection
- Accompanying fever, painful joints, conjunctivitis, or underlying cancer
- Raised white cell count on blood testing
- Improvement with systemic steroids and not with antibiotics
- Increased erythrocyte sedimentation rate (ESR)
Diagnostic histopathological features of acute febrile neutrophilic dermatosis are numerous polynuclear neutrophil inflammatory cells associated with broken-up neutrophils (leukocytoclasia) and swelling of cells lining blood vessels (endothelial cells). However other inflammatory patterns may be observed, eg mononuclear histiocyte cells. True vasculitis may occur in severe cases.
Blood tests in patients with acute febrile neutrophilic dermatosis may reveal:
- Raised erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), indicating systemic inflammatory disease
- Raised white cell count (neutrophil leukocytosis)
- p-ANCA (antineutrophil cytoplasmic antibody) or c-ANCA is sometimes present
Occasionally, acute febrile neutrophilic dermatosis is the presenting sign of a serious blood condition. A full blood count may reveal raised or reduced numbers of red cells, white cells and/or platelets. Further investigation may require bone marrow examination.
Treatment of acute febrile neutrophilic dermatosis
Treatment of acute febrile neutrophilic dermatosis usually results in rapid improvement in symptoms. Usually, systemic steroids, such as predniso(lo)ne, are prescribed in a dose of 30–60 mg daily. Within a few days the fever, skin lesions and other symptoms clear up. However, lower doses of corticosteroids are often required for several weeks to months to prevent relapse.
Several other medications may be tried when systemic corticosteroids are ineffective or contraindicated. Those reported to be useful include:
- Topical corticosteroids
- Intralesional corticosteroids
- Potassium iodide solution
- Non-steroidal anti-inflammatory drugs (indomethacin)
- Other biologic agents such as infliximab, adalimumab or etancercept
In some cases, acute febrile neutrophilic dermatosis is very resistant to treatment.
What is the outcome of acute febrile neutrophilic dermatosis?
Acute febrile neutrophilic dermatosis usually resolves eventually, without leaving a mark or scar, with or without treatment. Subcutaneous neutrophilic panniculitis can leave dents in the skin due to destruction of subcutaneous fatty tissue.
Generally there is a single episode of Sweet syndrome, but a third of patients may develop recurrent episodes. This is more likely in patients who have underlying myelodysplasia or cancer. Rarely, it may persist for months or years.
Severe ulcerative cases associated with malignancy persist, despite treatment.