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. In the case of infections, primarily infections of the upper respiratory tract or of the intestine (salmonellosis, yersiniosis) are present; non-tuberculous mycobacteriosis (NTM), chronic inflammatory bowel disease (CED), especially Crohn's disease, can also be causative.

Malignant underlying diseases (about 20%): Predominantly in hematological 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 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 high fever occurs 3-7 days before the skin symptoms.

• Integument: Development of reddish-livid, succulent, pressure-marked, infiltrated papules which confluent into nodules and plaques. The pronounced inflammatory oedema creates the impression of blistering ("illusion of vesiculation"), sometimes with the formation of small blisters. Later pustular formation is possible. Central brightening and marginal progression leads to the formation of bizarrely shaped, abnormal plaques. No formation of ulcerations, no scarring of the skin lesions.
• Extracutaneous manifestations: Polyarthritis (in about 50-60% of patients) with rapidly changing, very painful swelling of the large and middle joints. Frequently fever (44%), myalgia, nephritis, hepatitis, conjunctivitis (about 30%) or iridocyclitis, inflammatory bowel diseases, sterile osteomyelitis; rarely aseptic meningitis, rarely pancreatitis.

Highly accelerated SPA and increased CRP (in approx. 80-90% of patients), leukocytosis (44%) with neutrophilia (63%) and left-shifting; lymphopenia. Pathologically found are: alkaline phosphatase (approx. 40-50%), transaminases (15-20%), anaemia (30-50% in malignant basic diseases), 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).

Flag. Clinical exclusion of chronic myeloid leukemia is required.

Schematizing the following algorithm can be established:

• Clinical:
  • Erythema exsudativum multiforme: In the early phase of the disease clinically-morphologically similar picture. However, erythema exsudativum multiforme usually lacks fever and neutrophil leucocytosis! In the full picture of the erythema exsudativum multiforme with development of the EEM coccardium, DD becomes clear.
  • Polymorphic light dermatosis: Occurs after UV exposure (sun pattern!), no fever, no neutrophil leucocytosis, severe itching.
  • Acute urticaria: Clinical determination of the wheals (volatility of the efflorescences is proven by marking). No fever! No neutrophil leukocytosis.
  • Urticaria vasculitis: Pronounced chronicity over many years (untypical for Sweet syndrome). Exanthema characterized by fever attacks, small spots, maculopapular, itchy or painful. Neutrophilic leukocytosis is possible. Frequently arthralgias and arthritides (also possible in the Sweet Syndrome). Frequently swelling of lymph nodes. Possibly positive ANA and signs of systemic lupus erythematosus. Histological signs of vasculitis are diagnostic.
  • Subacute cutaneous lupus erythematosus: Especially in highly acute course with disseminated plaques a similar picture can develop (especially in erythema exsudativum multiforme-like lesions). The neutrophil leucocytosis is always missing in the blood count. Histology and immunohistology are diagnostic.
  • Varicella in adults: Pay attention to the typical distribution pattern of varicella (incl. capillitium, oral mucosa). This distribution is completely untypical for the Sweet Syndrome. The prominent development of the vesicles or blisters speaks against the Sweet Syndrome (vesicles in Sweet Syndrome are multilocular within the lesions!) No neutrophil leukocytosis!
  • Drug exanthema (maculo-papular): No fever, no neutrophil leukocytosis. No marked feeling of illness. Connection with altered or intercurrent drug administration can often be established.
  • Bullous pemphigoid: In some cases no development of the clinically pathological blisters. Thus the clinical leading symptom "bulging (firm) bladder" and the clear clinical assignment to the blister-forming diseases is omitted. No fever, no neutrophil leucocytosis. Serology, histology and IF are conclusive.
• Histological:
  • Leucocytoclastic vasculitis: Clinically mostly excluded. Histologically decisive is the proof of vasculitis (swelling of the vessel wall) with leukocytoclasia and perivascular nuclear dust.
  • Erythema elevatum diutinum: Rare disease! In the early stage always signs of leukocytoclastic vasculitis with leukocytoclasia and nuclear dust and fibrin in the vessel walls. Epidermis and skin appendages remain unaffected. Clinically, the acuteity of Sweet's syndrome is missing.
  • 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 abscess with dense diffuse granulocytic infiltrate.
  • Urticaria: Only slight infiltrate; no significant involvement of neutrophilic granulocytes.
  • Urticarial vasculitis: Differently intensive characteristics of leukocytoclastic vasculitis. In many patients (especially if not relapsing-active), however, only superficial and profound perivascular round cell infiltrates are found, to which eosinophilic granulocytes are added in varying densities.
  • Erysipelas: Only moderately pronounced infiltrates of neutrophil granulocytes, especially in the upper and middle dermis.
  • Eosinophilic cellulitis (Wells syndrome): Focal dense infiltrates, perivascular and interstitially stored, almost exclusively from eosinophilic granulocytes. Focal, polygonally bounded eosinophilic flame figures in the dermis.

• If necessary, in the presence of an infection, treatment of the underlying disease with consistent systemic antibiotics.
• Glucocorticoids: Very good response rate! Initial medium dosage, e.g. prednisone 1.0-1.5 mg/kg bw/day i.v. or p.o. over 4-6 weeks then gradual reduction depending on response to therapy. Risk of relapse if the dose falls below a critical threshold dose.
• Alternatively: acetylsalicylic acid and indomethacin in medium dosage (indomethacin is particularly effective for frequently occurring arthralgias).
• Alternatively: Colchicum 2-3 times/day 0.6 mg p.o. or DADPS 2 times/day 50 mg p.o. Own experience is not very positive regarding the latter therapies. Therefore, in our opinion, there are no effective alternatives to glucocorticoid treatment.
• Successful therapy 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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