Acute febrile neutrophilic dermatosis (Sweet syndrome)

What is acute febrile neutrophilic dermatosis?

Acute febrile neutrophilic dermatosis is a rare skin condition characterised by a sudden onset of painful, inflamed skin lesions associated with fever.

Acute febrile neutrophilic dermatosis also has the eponymous name, Sweet syndrome, 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 typically occurs in women aged between 30-60 years old. It can also develop in men, children (rarely), and the elderly. There is also no identifiable racial preference.

Most affected individuals have underlying associated conditions.

What causes acute febrile neutrophilic dermatosis?

The exact cause of this condition remains unknown, but possible causes are:

• Genetic risk, such as HLA-B54, in the Japanese population.
• Hypersensitivity reaction to bacteria, viruses, or tumours, causing inflammation in the body and skin.
• Imbalance of certain cytokines (proteins) within the immune system, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-1 (IL-1).

The syndrome can manifest in three clinical settings:

• Classical (or idiopathic) – associated with infections, inflammatory bowel disease (IBD) or pregnancy.
• Malignancy-associated – frequently acute myeloid leukaemia (AML).
• Drug-induced – commonly G-CSF, tretinoin, sulfamethoxazole + trimethoprim, bortezomib, and azathioprine.

What are the clinical features of acute febrile neutrophilic dermatosis?

Acute febrile neutrophilic dermatosis may occur once or repeatedly. 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
• Headache
• Sometimes other parts of the body are affected, including bones, nervous system, kidneys, intestines, liver, heart, lungs, muscles, and spleen.

Skin lesions may be few or numerous. They are characteristically tender and may persist from days to weeks. Lesions commonly affect the face, neck, and upper extremities. In some patients, they arise only in sun-exposed areas.

Annular plaque on the neck due to acute febrile neutrophilic dermatosis - there is a pseudovesicular edge 

Acute febrile neutrophilic dermatosis on the neck (AFND-patient4)

Plaques of tender acute febrile neutrophilic dermatosis on the neck 

Annular lesions of acute febrile neutrophilic dermatosis 

Oedematous lesions on the fingers due to acute febrile neutrophilic dermatosis of the dorsal hands (AFND-patient2)

Sweet syndrome 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) - the pseudovesicles are often visible at the periphery annular lesions
• Annular (ring-shaped) lesions.
• Erosions and ulcers resembling atypical pyoderma gangrenosum.

 

 

 

In some patients, acute febrile neutrophilic dermatosis can affect the eyes and the inner lining of the mouth, including the tongue and lips, causing erosions or ulcerations.

How do clinical features vary in differing types of skin?

Sweet syndrome can present with dusky or a more violaceous colouration in darker skin. Post-inflammatory hyperpigmentation (area of darker skin after wound healing) is also more prominent and lasts longer in darker skin.

How is acute febrile neutrophilic dermatosis diagnosed?

There is no specific testing for acute febrile neutrophilic dermatosis but, there is a diagnostic criterion developed to help identify it. To diagnose Sweet syndrome, two major criteria combined with two of the four minor criteria must be met.

Major criteria

1. Sudden onset of tender plaques or nodules
2. Histology (tissue analysis): neutrophilic infiltrate in the dermis without vasculitis

Minor criteria

1. Fever >38°C
2. Illness preceded or associated with infection, inflammatory disorder, malignancy or pregnancy
3. Increased inflammatory markers (CRP/ESR) and white cell count (WCC) with neutrophil (type of white blood cell) predominance
4. Positive response to corticosteroids

The following tests can be performed to determine if an underlying cause of Sweet syndrome is present, especially occult malignancies:

• Auto-immune screening
• HIV testing
• Thyroid function test
• Rheumatoid factor
• Antistreptolysin-O antibody titer
• Malignancy screening: lymph node examination, examination of breasts and pelvis in females, testicles in males, CT- thorax abdomen and pelvis if indicated.

It is also worth noting that there are several clinical and histopathological (tissue changes related to a disease) variants of Sweet syndrome which may alter management.

Clinical variants

1. Bullous Sweet syndrome
2. Cellulitis-like Sweet syndrome
3. Necrotising Sweet syndrome
4. Neutrophilic Dermatosis of the dorsal hands

Histological variants

1. Cryptococcoid Sweet syndrome
2. Histiocytoid Sweet syndrome
3. Subcutaneous Sweet syndrome

What is the differential diagnosis for acute febrile neutrophilic dermatosis?

• Allergic contact dermatitis
• Drug eruptions
• Cellulitis
• Herpes simplex
• Panniculitis
• Pyoderma gangrenosum
• Erythema nodosum
• Erythema multiforme
• Lupus erythematosus
• Behçet's disease

What is the treatment for acute febrile neutrophilic dermatosis?

Treatment of acute febrile neutrophilic dermatosis usually results in rapid improvement in symptoms. Usually, systemic corticosteroids such as predniso(lo)ne, are prescribed in a dose of 30–60 mg daily. The fever, skin lesions and other symptoms clear up within a few days. However, lower doses of corticosteroids are often required for several weeks to months to prevent reoccurrence.

Several other medications may be tried when systemic corticosteroids are ineffective or contraindicated. Those reported to be useful include:

• Topical corticosteroids
• Intralesional corticosteroids
• Colchicine
• Potassium iodide solution
• Dapsone
• Non-steroidal anti-inflammatory drugs (indomethacin)
• Ciclosporin
• Anakinra
• Other biologic agents such as infliximab, adalimumab, etanercept and spesolimab
• Minocycline
• Mycophenolate
• Clofazimine
• Thalidomide

In some cases, acute febrile neutrophilic dermatosis is resistant to treatment.

How do you prevent acute febrile neutrophilic dermatosis?

Prior knowledge and high index of suspicion in high-risk patients (with associated disease such as IBD, AML or taking commonly associated medications), and early management may help prevent the symptoms or complications associated with Sweet syndrome.

What is the outcome for acute febrile neutrophilic dermatosis?

Acute febrile neutrophilic dermatosis usually resolves eventually, without leaving a mark or scar, with or without treatment though the lesions may persist for weeks to months. Generally, there is a single episode of Sweet syndrome, but approximately 50% of patients may develop repeated episodes. This is more likely in idiopathic or in patients with underlying cancer. Rarely, it may persist for years.

What are the complications of acute febrile neutrophilic dermatosis?

• Secondary impetiginisation (bacterial infection)
• Scarring
• Skin atrophy (skin thinning)