(Sweet´s Syndrome)

 

 History

Sweet's Syndrome (Acute Febrile Neutrophilic Dermatosis) has been first described by the English dermatologist Robert Douglas Sweet from Plymouth in 1964 following the observation of 8 female patients. The disease has been commonly termed Sweet's Syndrome, afterwards, and experienced increasing awareness during the last ten years. It is unclear so far, whether the more than 500 cases in the literature reports are due to an increasing incidence of this specific kind of reaction. But it is generally accepted, that Sweet's Syndrome is a clinically, as well as histologically clearly described entity and represents rather a frequent dermatological disease than a rarity.

 

 

Epidemiology

Male/female = 1:3. Incidence has been estimated to be 2.7 cases per million population in Scotland. In Geneva, Switzerland, a highly variable yearly incidence has been interpreted as a clue to a possible infectious cause. The incidence of patients peak in spring and autumn suggesting seasonality in the occurrence of Sweet's Syndrome. Age: Sweet's Syndrome occurs in three different affected groups: Children during the first two years, and between the seventh and eleventh years of life, Females between 30 and 79, and males between 50 and 79 years of age. Occurrence: 1. Classic: occurrence 4-14 days after an unspecific infection of the upper respiratory or the gastrointestinal tract, or after vaccination. 2. Idiopathic cases are defined as having no antecedent infection in the patient's history and that no associated disease could be diagnosed after a comprehensive diagnostic program. 3. Parainflammatory: cases are defined as being characterized by an accompanying inflammatory disease such as Yersinia infection or rheumatoid arthritis. 4. Para- or Preneoplastic: Prior to or in the course of a hemoproliferative disorder or a solid carcinoma. 5. Pregnancy. 6. Only rarely Sweet's Syndrome represents an allergic adverse drug reaction. There are increasing number of reports about Sweet's Syndrome after G-/GM-CSF immunotherapy treatment. Regarding occurrence of Sweet's Syndrome and frequency, the occurrences of Sweet's Syndrome in 176 patients in the literature show:

 

Classic/idiopathic 71%

Parainflammatory 16%

Paraneoplastic 11%

Pregnancy 2%

 

Clinical Findings, Diagnosis, and Laboratory Results

Sweet's Syndrome is normally a clinical diagnosis. The occurrence of multiple painful, sharply demarcated, raised erythematous plaques distributed on the face, neck, upper chest and back as well as on the extremities is characteristic. These plaques are painful and burning but characteristically not itching. The size is normally a few centimeters, but large plaques may develop. The surface of these plaques may exhibit a mamillated appearance ("relief of a rocky island") with pseudovesiculation, pseudopustulation, and pustules, and in rare instances, heavy blistering may occur. The color of the plaques is red to blue-red, sometimes with a faint central white-yellow discoloration leading to the impression of a target lesion similar to erythema multiforme (EM). A subtype of Sweet's Syndrome with a single or few lesions often manifests itself on the face and has been termed "localized Sweet's Syndrome". Fever and leukocytosis are often absent in these patients. Oral lesions occur in about 30% of the cases and may facilitate the diagnosis. On the lower legs, in 12-30% of the patients lesions clinically and histologically identical to erythema nodosum occur. In typical cases, the general condition of the patient is affected by malaise and recurrent fever periods. Conjunctivitis and polyarthralgia may be additional symptoms. Laboratory findings can also contribute to the diagnosis. Rarely, internal organs such as lung, liver, kidney, and central nervous system may be involved and lead to corresponding laboratory findings. In certain studies, presence of ANCA is not a feature of Sweet's Syndrome.

 

Laboratory parameters in Sweet's Syndrome

Elevated Erythrocyte sedimentation rate (ESR) 100%

Leukocytosis 60%

Segmented-nuclear neutrophils + stabs > 70% 79% Shift to the left (> 7% stabs) 50% Lymphocytes < 25% 50%

Hemoglobin < 13.0 g/dl 54%

a2-globulins > 10% 90%

C-reactive protein elevated 84%

Alkaline phosphatase > 103 IU/ml 46%

Anti-neutrophilic-cytoplasmic-(auto) antibodies (ANCA) (n=10) 0%

 

Diagnostic criteria for Sweet's Syndrome. (Both major and two minor criteria are needed)

 

Major criteria

1. Abrupt onset of tender or painful erythematous plaques or nodules occasionally with vesicles, pustules or bullae. 2. Predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis.

 

Minor criteria

1. Preceded by an unspecific respiratory or gastrointestinal tract infection or vaccination or associated with: Inflammatory diseases as chronic autoimmune disorders, infections etc. Hemoproliferative disorders or solid malignant tumors Pregnancy. 2. Accompanied by periods of general malaise and fever (>38°C) 3. Laboratory values during onset (three out of four necessary): ESR > 20mm n.W., C-reactive Protein positive, segmented-nuclear neutrophils and stabs > 70% in peripheral blood smear, leukocytosis > 8,000. 4. Excellent response to treatment with systemic corticosteroids or potassium iodide.

 

Differential diagnosis

Sweet's Syndrome, especially pustular forms, is often diagnosed as a septic process. Antibiotics, however, fail to improve the disease. Erythema multiforme and a multiform drug reaction can resemble Sweet's: Erythema multiforme shows more males, and may be associated with Herpes simplex infection or a new drug. Histological findings in a fresh lesion (less neutrophils) can rule out Erythema multiforme, so can laboratory parameters (Erythema multiforme has a lower ESR, less neutrophils in blood smear, no lymphopenia, no moderate anemia). In disseminated erythema nodosum: Histology is classic. In erythema elevatum et diutinum, lesions, localization, histology, and direct immunofluorescence are different than in Sweet's. In Behcet's disease there are differences regarding aphthae, uveitis, thrombophlebitis, histology, and direct immunofluorescence. Pyoderma gangrenosum shows ulcerated lesions, localization is the usual presentation, histology is non-specific in developed lesions. Halogenoderma: Shows similar pictures in early phases, both clinically and histologically. In more advanced states, you see clinically vegetating lesions and, histologically, more eosinophils and vasculitis. Chronic neutrophilic plaques may appear in Bowel-bypass syndrome: These may be clinically and histologically identical and these entities may belong to the spectrum of Sweet's Syndrome. "Pustular vasculitis of the hands": Shows no clear cut discrimination. These cases may also belong to the spectrum of Sweet's Syndrome. Histology: Shows an infiltrate consisting of mononuclear cells and numerous neutrophils with leukocytoclasis, a marked vasodilatation, and swelling of the vascular endothelium with moderate erythrocyte extravasation, and prominent edema of the upper stratum corneum frequently leading to the formation of vesicles or bullae. In pustular vasculitis of the hands, the inflammatory cells exhibit a band-like infiltration throughout the upper dermis. Sometimes, numerous neutrophils immigrate into the epidermis and may form subcorneal pustules. Perivascular mononuclear infiltrates may affect the deeper corneum, and the subcutaneous tissue in some cases. Intravascular microthrombi and extensive destruction of the vessel walls are not a feature of Sweet's Syndrome, but careful examination of Sweet's Syndrome lesions sometimes reveals vasculitis-like findings for single vessels. In later stages, histiocytes and lymphocytes accompanied by leukocytoclasis predominate in the infiltrate. Regressing lesions of Sweet's Syndrome comprise of less neutrophils and are similar to late stage lesions. Erythema nodosum-like lesions: Show a septal panniculitis with Miescher's granulomas and some characteristic neutrophils. A few reports describe a subtype of Sweet's Syndrome characterized by the occurrence of neutrophil-rich infiltrates in the subcutaneous tissue.

 

Pathogenesis

The pathogenesis of Sweet's Syndrome is still unknown. It is clear that this disease represents a reactional state, but the precise pathomechanisms have not been elucidated. Four principle hypothetical aspects have been suggested. None of them have been definitely proven, so far, but convincing evidence suggests that Sweet's Syndrome is a cytokine- ( e.g. IL-1, IL-8, G-CSF, GM-CSF) T-cell-mediated disease with secondary and only temporary activation and participation of neutrophils and that immune complex deposition does not play a major role in the initial state.

 

Associated diseases

An increasing variety of associated diseases or conditions may be associated with Sweet's Syndrome. The major parainflammatory diseases are autoimmune and infectious disorders. Sweet's Syndrome associated with hemoproliferative diseases may precede the underlying disorder for years and in general, worsens the prognosis. The rising number of cases found in association with solid carcinomas supports the concept that these tumors did not occur by chance. In contrast to the majority of other paraneoplastic syndromes, however, Sweet's Syndrome can occur so early in the development of these cancers that curative therapy is possible. No fundamental clinical and histopathological differences between classical and paraneoplastic Sweet's Syndrome are known. But the female: male ratio in paraneoplastic Sweet's Syndrome is about 1:1, and thus, male patients have a higher risk to be affected by paraneoplastic Sweet's Syndrome. Paraneoplastic Sweet's Syndrome features no antecedent respiratory infection. There is heterogeneity of cutaneous lesions with blistering and/or ulceration. Paraneoplastic Sweet's Syndrome features abnormal laboratory results (e.g. anemia, thrombocytosis, thrombocytopenia) which may enforce a thorough diagnostic investigation. A close follow up of all cases advisable.

 

Associated diseases and conditions

Sweet's Syndrome is associated with parainflammatory diseases, autoimmune diseases, Behcet's disease, Crohn's disease, Ulcerative colitis, Sjörgrens syndrome, LE, Rheumatoid arthritis, Thyroiditis, MCTD, Sarcoidosis, Infections, Yersiniosis, Focal infections ( e.g. tonsillitis), Toxoplasmosis, Histoplasmosis, Ureaplasmosis, Tuberculosis, Paraneoplastic, Leukemia and Lymphoma, AML, AMML, ALL, Myelodysplasia, polycythemia, myeloid metaplasia, CML, CLL, Multiple myeloma, Hairy cell leukemia, Non-Hodgkin-lymphomas, Solid tumors, Carcinoma of the breast, prostate, uterus and vagina, colon, stomach, rarely others, Other associated conditions include vaccination and therapy with growth factors,

 

Therapy

Standard treatment of Sweet's Syndrome is the oral administration of prednisolone. The dose may be reduced within three weeks. All lesions, symptoms, and pathological laboratory findings may normalize within 14 days. A number of non-steroidal drugs, especially potassium iodide, has been used alternatively, but no comparative studies are available so far. In one series, two cases with cancer-associated Sweet's Syndrome died from acute pneumonias. Six cases experienced a chronic relapsing course. In one case, relapses stopped after surgical treatment of a prostatic carcinoma about one year later. In other cases, clofazimine was given at a dose of 200 mg/d and 100 mg/d for four weeks, respectively, and observed a good remission of the Sweet's Syndrome. Potent topical steroids may also be of value for minor lesions.

Nonsteroidal treatment modalities for Sweet's Syndrome:

Drugs and Recommended initial doses include:

Potassium iodide 900 mg/day

Colchicine 1.5 mg/day

Dapsone 100-200 mg/day

Clofazimine 200 mg/day

Cyclosporin A 5-10 mg/kg/ body weight /day

Indomethacin 50-100 mg/day

Naproxen 750 mg/day

Doxycycline 200 mg/day