Sweet syndrome L98.2

Sweet 1964

Rare, acute, high-fever systemic disease with disturbance of the general condition, arthralgias, neutrophilic leukocytosis and an exanthema consisting of disseminated, painful, succulent, papular or plaque-like elevations.

The Sweet syndrome is the prototypical representative of the so-called"neutrophilic dermatoses".

Depending on the aetiology, 5 groups can be distinguished:

1. Classical or idiopathic type, according to the initial description of Sweet
2. Paraneoplastic type
3. Infectious or autoimmune disease associated type
4. drug-induced type
5. Pregnancy-associated type.

Cause often unexplained (idiopathic Sweet syndrome).

Infections: Interpretation as infection - (about 60-80% of cases) allergic event. The infections are mainly infections of the upper respiratory tract or intestine (salmonellosis, yersiniosis); also non-tuberculous mycobacteriosis (NTM), chronic inflammatory bowel disease (CED), especially Crohn's disease, can be causative.

Malignant underlying diseases (approx. 20%): Predominantly in hematologic proliferative processes, especially in acute myeloid leukemia (AML), in myelodysplastic syndrome, here to be understood as progression of the disease (Vignon-Pennamen MD et al. 2017), less frequently in urogenital malignancies. Sweet syndrome often precedes the diagnosis of malignancy.

Drugs: Triggered by the following drugs known: antibiotics (clindamycin, minocycline, cotrimoxazole), carbamazepine, granulocyte colony-stimulating factor (e.g. filgrastim), nitrofurantoin, retinoic acids, azathioprine, chloroquine, hydralazine, imatinib, bortezomib, contraceptives. The proportion of drug-induced Sweet syndromes is estimated to be about 5%. Skin lesions occur approximately 7-8 days after initial drug use (Walker DC et al 1996).

Pathogenetically, activation of neutrophil granulocytes by dermally deposited immune complexes with subsequent activation of neutrophil-associated mediators (granulocyte [PMN] elastase, granulocyte colony-stimulating factor [G-CSF]) is discussed. Other cytokines involved: IL-1, IL-6, IL-8, interferon gamma.

Genetic Sweet syndromes: Majeed syndrome (OMIM: 609628) is characterized by an autosomal recessive mutation in the LPIN2 gene. This gene encodes the phosphatidate phosphatase LPIN2. Majeed syndrome is inconstantly associated with Sweet syndrome.

Especially on the face, neck, extensor sides of the arms and legs, torso.

Rarely mucous membrane involvement.

Usually occurs 3-7 days before the skin symptoms flu-like prodromal stage with fatigue, arthralgein and high fever (fever may be absent).

• Integument: Sudden development of reddish-livid, succulent, pressure-dolored, infiltrated papules that confluence into nodules and plaques. The pronounced inflammatory edema initially gives the impression of blistering ("illusion of vesiculation"). In later stages, confluent pustules develop. Central lightening and marginal progression lead to the formation of anular, bizarrely shaped, bright red plaques. No formation of ulcerations, no scarring of the skin lesions.
• An acral variant has been described.
• Extracutaneous manifestations: Polyarthritis (in about 50-60% of pat.) with rapidly changing, very painful swellings of the large and medium-sized joints. Frequent fever (44%), myalgias, nephritis, hepatitis, conjunctivitis (about 30%) or iridocyclitis, inflammatory bowel disease, sterile osteomyelitis; rarely aseptic meningitis, rarely pancreatitis.
• Neutrophilic dermatosis of the back of the hand" has been described as a (localized) minus variant of Sweet's syndrome.

Strongly accelerated ESR and elevated CRP (in approx. 80-90% of patients), leukocytosis (44%) with neutrophilia (63%) and left shift; lymphopenia. Pathological findings include: alkaline phosphatase (about 40-50%), transaminases (15-20%), anemia (30-50% in underlying malignancies), thrombocytopenia, proteinuria, HLA-Bw54 detection (20-30%). Positive detection of p- ANCA has been described.

Papillary edema to subepidermal blistering; spongiosis or subcorneal vesicles or pustules are possible but rare. The epidermis is usually unremarkable. Very dense infiltration of the upper and middle dermis, occasionally the subcutis, consisting of neutrophilic granulocytes (clonality of neutrophilic infiltrates has been described) without signs of leukocytoclastic vasculitis. Leukocytoclasia is mild or absent. Erythrocyte extravasations are seen. In later stages, the infiltrate changes to lymphocytes and histiocytes.

Histologic pattern: Superficial, diffuse, neutrophilic dermatitis.

Variant: Histiocytoid Sweet syndrome with diffuse infiltrate of immature neutrophilic mononuclear histiocytoid appearing granulocytes (promyelocytes: myeloperoxidase positive).

Variant: Subcutaneous Sweet syndrome with diffuse infiltrate of neutrophilic leukocytes in subcutaneous adipose tissue. No evidence of septal panniculitis (DD: erythema nodosum).

Notice. Clinical exclusion of chronic myeloid leukemia is required.

Schematizing the following algorithm can be established:

Main criteria

• Febrile exanthema with succulent papules, plaques and nodules
• Histology: neutrophilic dermatitis

Secondary criteria

• No prodromi
• Previous infection
• Fever >380C
• ESR > 20mm/h
• Blood count: neutrophilic leukocytosis with left shift
• Prompt response to glucocorticoids

Clinical:

• Erythema exsudativum multiforme: In the early phase of the disease, the clinical and morphological picture is similar. However, fever and neutrophilic leukocytosis are usually absent in erythema ex sudativum multiforme! In the full-blown erythema exsudativum multiforme with formation of the EEM cocardia, the DD becomes clear.
• Polymorphous light dermatosis: Occurring after UV exposure (sun pattern!), no fever, no neutrophilic leukocytosis, severe pruritus.
• Acute urticaria: Clinical determination of wheal (prove volatility of efflorescences by marking). No fever! No neutrophilic leukocytosis.
• Urticarial vasculitis: Pronounced chronicity lasting years or more (atypical of Sweet's syndrome). Small-spotted, maculo-papular, pruritic or painful exanthema characterized by episodes of fever. Neutrophilic leukocytosis is possible. Frequent arthralgias and arthritides (also possible in Sweet syndrome). Frequent lymph node swelling. Possibly positive ANA and signs of systemic lupus erythematosus. Histologically, signs of vasculitis are diagnostic.
• Subacute cutaneous lupus erythematosus: Especially in highly acute course with disseminated plaques, a similar picture may develop (especially in erythema exsudativum multiforme-like lesions). Neutrophilic leukocytosis is always absent from the blood count. Histology and immunohistology are diagnostic.
• Adultvaricella: Look for the typical distribution pattern of varicella (incl. capillitium, oral mucosa). This distribution is completely atypical for Sweet syndrome. The prominent development of the vesicles or even blisters speaks against Sweet's syndrome (vesicles in Sweet's syndrome are multilocular within the lesions!). No neutrophilic leukocytosis!
• Drug exanthema (maculo-papular): No fever, no neutrophilic leukocytosis. No prominent feeling of illness. Association with altered or intercurrent drug administration can often be established.
• Bullous pemphigoid: In some cases, no formation of the clinically landmark blisters. This eliminates the leading clinical symptom of "bulging (firm) blister" and the clear clinical assignment to the blistering diseases. No fever, no neutrophilic leukocytosis. Serology, histology, and IF are conclusive.

Histology:

• Leukocytoclastic vasculitis: Usually excludes clinically. Histologic evidence of vasculitis (vessel wall swelling) with leukocytoclasia and perivascular nuclear dust is crucial in this case.
• Erythema elevatum diutinum: Rare disease! In early stage always signs of leukocytoclastic vasculitis with leukocytoclasia and nuclear dust and fibrin in the vessel walls. Epidermis and skin appendages remain uninvolved. Clinic lacks the acuity of Sweet's syndrome.
• Rheumatoid neutrophilic dermatitis: Dense, interstitial, dermal, neutrophilic infiltrate, no evidence of vasculitis; focal epitheliotropy with spongiotic vesiculation of pustular formation possible.
• Pyoderma gangraenosum: Ulceration and abscessation with dense diffuse granulocytic infiltrate.
• Urticaria: Only minor infiltrate; no significant involvement of neutrophilic granulocytes.
• Urticarial v asculitis: Variable intensity features of leukocytoclastic vasculitis. However, in many patients (especially when not relapsing), only predominantly superficial and profound perivascular round cell infiltrates are found, with eosinophilic granulocytes admixed at varying densities.
• Erysipelas: Only moderately marked infiltrate of neutrophilic granulocytes mainly in the upper and middle dermis.
• Eosinophilic cellulitis (Wells syndrome): Focally dense, perivascular and interstitial infiltrates, almost exclusively of eosinophilic granulocytes. Focal, polygonal, eosinophilic flame figures in the dermis.

If necessary, treatment of the underlying disease with consistent systemic antibiotics in the presence of an infection.

Glucocorticoids: Very good response rate! Initial medium dosage, e.g. prednisone 1.0-1.5 mg/kg bw/day i.v. or p.o. for 4-6 weeks then gradual reduction depending on response to therapy. Risk of recurrence if dose falls below critical threshold.

Alternative: acetylsalicylic acid and indometacin in medium dosage; (esp. indometacin is effective for common arthralgias).

Alternative: Colchicum 2-3 times/day 0,6 mg p.o. or DADPS 2 times/day 50 mg p.o. Own experiences are not very positive concerning the last mentioned therapies. Thus, in our opinion, there are no effective alternatives to treatment with glucocorticoids.

Successful therapeutic approaches have been described with ciclosporin A, dapsone and IVIG.

Favourable, even without therapy healing within weeks to months. Under therapy dramatic improvement. However, 50% of patients relapse after therapy-induced or spontaneous healing. In drug-induced sweet syndrome, the exanthema heals within 3-30 days after discontinuation of the drug in question. The fever subsides within 3-5 days.

Due to its histopathology characterized by neutrophil granulocytes, the Sweet Syndrome together with other dermatoses is classified as a so-called neutrophilic dermatosis.

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