1.1.4.3 Sweet's syndrome (acute neutrophilic dermatosis)

Acute febrile neutrophilic dermatosis, Gomm-Button disease.

Sweet’s syndrome is a disorder characterized by a variety of clinical and histological findings, which include fever, neutrophilia, erythematous plaques or nodules, and a diffuse dermal neutrophilic infiltrate. Additional criteria include absence of infection or histopathological changes of vasculitis and responsiveness to corticosteroids.

Pathogenesis is unknown. Possible hypersensitivity reaction to a variety of eliciting bacterial, viral, or tumor antigens that may trigger neutrophil activation and infiltration. Possible role of activating cytokines and chemokines such as IL-1, IL-3, IL-6, IL-8, G-CSF, GM-CSF, and interferon-gamma.

Most cases of Sweet’s syndrome are considered to be idiopathic, but could also be associated with different disorders:

• Malignancy (10-20%): Myeloproliferative disorders (myelodysplasia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, monoclonal gammopathy, lymphoma) and rarely with solid tumors.

• Inflammatory and autoimmune disorders: Inflammatory bowel disease (ulcerative colitis or Crohn disease), rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, Sjogren syndrome, relapsing polychondritis, and thyroid disease (both Graves disease and Hashimoto thyroiditis), Behcet disease, dermatomyositis.

• Infectious diseases: HIV, viral hepatitis, tuberculosis, upper respiratory tract infections (mostly Streptococcus) or Chlamydia infection.

• Drugs: G-CSF, antibiotics (minocycline, nitrofurantoin, trimethoprim-sulfamethoxazole, norfloxacin, ofloxacin), antihypertensives (hydralazine, furosemide), NSAIDs (diclofenac, celecoxib), immunosuppressives (azathioprine), antiepileptics (carbamazepine, diazepam), anti-cancer (bortezomib, imatinib mesylate, ipilimumab, lenalidomide, topotecan, vemurafenib), tyrosine-kinase inhibitors, antipsychotics (clozapine), anti-thyroid (propylthiouracil).

• Pregnancy

Some genetic factors such as HLA-B54. MEFV gene mutations in familial Mediterranean fever patients, and chromosome 3q abnormalities have been observed in patients with Sweet’s syndrome.

Acute febrile episode associated with well-defined edematous, tender erythematous plaques or nodules accompanied by fever and constitutional symptoms (myalgia, fatigue, headache).

The lesions appear as solitary or multiple, 0,5 to 12 cm, red or purple-red, papules or nodules with a pseudovesiculous appearance. Larger lesions may develop into plaques. Central clearing may lead to annular patterns. The classical (idiopathic) form is often preceded by an upper respiratory or gastrointestinal tract infection.

In patients with malignancy-associated Sweet’s syndrome, the lesions may adopt atypical clinical patterns (bullous, ulcerated or mimicking pyoderma gangrenosum). Other clinical variants include localized neutrophilic dermatosis of the dorsal hands, subcutaneous, cellulitic, or giant cellulitic-like, and necrotizing Sweet’s syndrome. Lesions on the legs can mimic erythema nodosum (in fact both conditions can be associated in the same biopsy).

Sweet’s syndrome lesions can uncommonly be associated with extracutaneous systemic manifestations (especially in the setting of an underlying malignancy) including arthralgias and non-erosive inflammatory arthritis (30-60%), ocular inflammation, (conjunctivitis, episcleritis, uveitis), myocarditis, multifocal sterile osteomyelitis, alveolitis, hepatitis, pleural effusions, and aseptic meningitis

The eruption is often distributed asymmetrically. The most frequent lesion locations are the upper extremities, face and neck. They can also be present on the chest, back, and lower extremities.

Peripheral leukocytosis (> 8000/mm3) with neutrophilia (> 70%). Elevated markers of inflammation (erythrocyte sedimentation rate and C-reactive protein).

Diffuse dense dermal neutrophilic infiltrates in the upper dermis and marked edema of the dermal papillae. Leukocytoclasia may be present. No vasculitic changes are observed. No epidermal involvement although spongiosis and subcorneal pustule formation may be present. In rare instances, the inflammation may extend to involve the subcutis, usually mimicking erythema nodosum.

Histiocytoid Sweet’s syndrome is a variant and includes immature myeloid cells (histiocytoid cells), sometimes atypical monocuclear cells (in patients with an underlying myelodysplastic syndrome).

The diagnosis is established on the basis of characteristic clinical and histopathological findings. Histopathological features are a requirement for the diagnosis of Sweet’s syndrome. An infectious disorder should be ruled out.

Diagnostic criteria for Sweet’s syndrome have been proposed. Diagnosis may be based on fulfilling both major criteria and two of the four minor criteria.

Major criteria:

1. Sudden onset eruption of tender, painful plaques or nodules

2. Dense neutrophilic infiltrate in the dermis without vasculitis

Minor criteria:

1. Fever >38C

2. Association with an underlying hematological or visceral malignancy, inflammatory disease, or pregnancy, or preceded by an upper respiratory or gastrointestinal tract infection or vaccination,

3. Elevation of three of the four laboratory values: a) erythrocyte sedimentation rate >20 mm/h: b) positive C-reactive protein; c) leukocyte count >8000; d) neutrophils >70%.

4. Excellent response to systemic corticosteroids or potassium iodide.

The diagnostic workup will include determining the underlying cause if any, especially malignancies. Complete blood cell count with leukocyte differential and platelet counts. Acute phase reactants (including erythrocyte sedimentation rate or C-reactive protein), biochemistry (liver and kidney function tests), and urinalysis will be assessed. Serologic evaluation will include antistreptolysin-O antibodies, rheumatoid factor, and thyroid function. Additional testing will be performed if extracutaneous involvement is clinically suspected.

Age-appropriate cancer screening, including colonoscopy, mammogram, and PAP smears, should be pursued.

• Febrile infectious disorders (bacterial, fungal, and mycobacterial).

• Cutaneous lesions of Sweet’s syndrome may mimic cellulitis, allergic contact dermatitis, hypersensitivity drug reactions,

• Erythema multiforme, erythema nodosum, pyoderma gangrenosum, leukocytoclastic vasculitis or leukemia cutis.

Systemic corticosteroids are the treatment of choice often achieving a rapid response. Other first-line oral systemic agents are potassium iodide, dapsone and colchicine. If corticosteroids are contraindicated or recurrence after tapering develops, steroid-sparing agents including methotrexate, doxycycline, indomethacin, chlorambucil, and cyclosporine could be prescribed. If an infectious condition is associated, specific treatment should be given. Treatment with anti-TNFα agents (adalimumab, infliximab), rituximab, anti-IL-1 agents (anakinra, rilonacept), and anti-IL-6 (tocilizumab) have been reported to be effective in isolated reports.

Topical high potency or intralesional corticosteroids or corticosteroids may be used for localized lesions.

Sweet’s syndrome typically follows a benign course, which, if untreated, can involute spontaneously without scarring in 5 –12 weeks.

Prognosis varies depending on the underlying associated disorder (if present).

Recurrences may occur usually in cases associated with an underlying inflammatory disease or hematologic malignancy.