Sweet's syndrome
(Acute febrile neutrophilic dermatosis)
Barbara Burrall, M.D.
Dermatology Online Journal 5(1):8

Abstract

Sweet's syndrome, or acute febrile neutrophilic dermatosis, is a condition characterized by the sudden onset of fever, leukocytosis, and tender, erythematous, well-demarcated papules and plaques which show dense neutrophilic infiltrates on histologic exam ination. Although it may occur in the absence of other known disease, Sweet's syndrome is often associated with hematologic disease (including leukemia), and immunologic disease (rheumatoid arthritis, inflammatory bowel disease). Treatment with systemic corticosteroids is usually successful.

Description

Sweet's syndrome, which was described by R.D.Sweet in 1964, is characterized by the sudden onset of fever, leukocytosis, and cutaneous eruption. The eruption consists of tender,erythematous, well-demarcated papules and plaques which show dense neutrophilic infiltrates microscopically. The lesions may appear anywhere, but favor the upper body including the face. [1] The individual lesions are often described as pseudovesicular or pseudopustular, but may be frankly pustular, bullous, or ulcerative. Oral and eye involvement (conjunctivitis or episcleritis) have been frequently reported. Arthralgias or arthritis are present in 33-62 percent. [2] Alveolitis, sterile osteomeyelitis, renal, hepatic, and central nervous system involvement have been reported.[3] The condition is more common in women and the mean age of onset is the mid to late fifties. Sweet's syndrome may last from one week to more than four years. Recurrance is common (25-37%).[2,3]

Clinical Presentations

Histopathology

A dense, perivascular, neutrophilic infiltrate is the hallmark of Sweet's syndrome.[4] Leukocytoclasis may be seen. Mononuclear cells and occasional eosinophils may be interspersed. The inflammatory cells form a band-like infiltrate in the papillary dermis. Dermal edema may be seen which may eventuate in subepidermal bulla formation. In neutropenic states the infiltrates may be less neutrophilic.

Etiology/Pathogenesis

The etiology of Sweet's syndrome is unknown, though it is presumed to be a type of hypersensitivity reaction which leads to stimulation of a cascade of cytokines that precipitate neutrophil activation and infiltration.[2,4,5, 6] A T-cell mediated immune response has been postulated.[7] HLA analyses have given variable results. Mizoguchi[8] described an increase in the frequency of HLA Bw54 in Japanese patients with Sweet's syndrome. However, recently in a series of 41 European, caucasian patients, no significant HLA associations were found.[9]

Differential Diagnosis

• Bowel bypass-related dermatosis
• Cellulitis/erysipelas
• Disseminated erythema nodosum
• Erythema elevatum diutinum
• Erythema multiforme
• Leukocytoclastic vasculitis
• Pyoderma gangrenosum

Associated Diseases

Von den Dreisch[2] summarized seven series and catagorized Sweet's syndrome cases into four groups: classic/idiopathic(71%), parainflammatory(16%), paraneoplastic(11%), and pregnancy-related(2%). However, more recently, in a large series of patients from Mayo Clinic, 54% had either a a malignancy or some type of hematologic disease.[3] The classic/idiopathic form has a significant female predominance whereas the malignant form does not.[2] In addition, paraneoplastic Sweet's syndrome is more likely to show slightly atypical lesions with more pustular/bullous forms as well as a greater localization to the upper body and face.[3] Paraneoplastic cases are most commonly associated with hematologic malignancies, though a wide variety of solid tumors are also found.[2] In one study, 160f patients who had no evidence of malignancy at presentation developed a malignancy within a year.[6] Hence, Sweet's syndrome may develop very early in the course of a malignancy, possibly at a curable stage. The Mayo Clinic series found 190f cases to have an associated immunologic disease which included relapsing polychondritis, rheumatoid arthritis, d ermatomyositis, non-specific connective tissue disease, and inflammatory bowel disease.[3] A variety of infections have been associated with the syndrome, and these include upper respiratory infections, urinary tract infections, viral pneumonia, Yersinia infection, typhus, salmonellosis, toxoplasmosis, tuberculosis and other mycobacterial infections, histoplasmosis, cytomegalovirus infections, tonsillitis, hepatitis, vulvovaginitis, and Helicobacter pylori infection.[2,3,11] In addition,drug-related cases have been recognized.[12] Granulocyte-Colony Stimulating Factor(G-CSF) has been reported to precipitate Sweet's syndrome as well as other neutrophilic dermatoses.[13,14,15] Chemotherapy with all trans-retinoic acid also stimulated Sweet's syndrome, which occurred concommitantly with the neutrophilic differentiation induced by the drug.[16] Trimethoprim-sulfamethoxazole, hydralazine, oral contraceptives, minocycline, Lithium, and furosemide have all been reported as offending drugs.[2,12,17] About 20f cases have been associated with pregnancy.[2,18] Onset was in the first or second trimester and most cases resolved spontaneously. No fetal mortality or morbidity occurred.

Laboratory/Special Examinations

The erythrocyte sedimentation rate is said to be elevated in most patients with Sweet's disease. The white blood cell cournt is said to be greater than 8000 in 80%, and greater than 10000 in 600f affected individuals.[2] Neutrophilia is less commonly found in association with drug-related causes.[12] Anemia and elevated alkaline phosphatase are present about half the time. The presence of anemia and low platelet count have been associated with an underlying malignancy.[10] Patients with Sweet's syndrome should undergo an age-appropriate work-up for malignancy. Earlier reports suggested an association of Sweet's disease with ANCA positivity, however further evaluation has cast doubt on this association.[2]

Management

Systemic corticosteroids have been the treatment of choice in most large series of patients reported.[2,3,19] Generally prednisone or prednisolone is used with an initial dose of 0.5-1.5 mg per kg per day. Reduction is begun within two to four weeks.[2] A good response can be anticipated with resolution of malaise within hours and mucosal lesions and fever within two days.[2] Skin lesions should resolve within one to four weeks.[2,3] However, recurrance is common (25%). Chronic relapsing disease is seen in about 15%.[2]

Topical and intralesional corticosteroids have frequently been used as adjunctive treatment along with systemic modalities. They are occasionally used as solo therapy and can be effective in mild cases.[3,4]

Indomethacin appears promising as an alternative to corticosteroids. It was first reported as useful in 1977.[20] Most recently,17/18 patients responded with clearing to indomethacin.(6) No recurrances were noted in a mean follow-up of 20 months. The dosage used was as follows: 150 mg per day for one week, 100 mg per day for two weeks. Indomethacin was then stopped. Fever and arthralgia were attenuated within 48 hours. The eruption clea red within 7-14 days. Naproxen was used successfully in one patient with CML.[21]

Some authors state that potassium iodide may be as effective as corticosteroids and that relapses may be less frequent.[2] However, the reports of KI use tend to be older and smaller numbers of patients were treated than in reports utilizing corticosteroids. Nevertheless, several studies have shown effective clearing with the use of KI.[19,22,23,24] In these studies, 900 mg per day was initiated. Symptoms improved within 48 hours and cutaneous lesions cleared within one week in most cases. In some cases the drug was withdrawn after only 2 weeks and no recurrance was seen.[22] Two patients developed a severe vasculitis that was attributed to KI.[19,25]

Several cases have been reported to respond to cyclosporine.[26,27,28] Initial doses have varied widely, from 2-10 mg per kg per day. Response was rapid (within one week). Tapering was difficult in some cases.

Joshi [29] reported two cases of successful treatment with doxycycline. Treatment was initiated with 100 mg BID. The lesions resolved within 3-4 weeks. Doxycycline was stopped after 6-8 weeks. No recurrances were noted in either patient, but follow up time was not stated.

A few cases have responded to the use of dapsone in doses of 100-200 mg per day.[3,30] It has also been used in combination with prednisone.[3,19] However, it has also been reported as a failure.[24]

Colchicine has been effective in a few case reports.[31,32] The initial dose used was 0.5 mg TID. Usually the drug could be stopped in seven days. Alternatively, the dosage could be tapered over three weeks. However, others found it to be ineffective.[3]

Clofazamine has been used in only a few cases, but appeared effective in doses of 200 mg per day.[2,33] Improvement began within one week, but it is unclear how long treatment was continued.

Pentoxifylline was given as a trial at 400 mg TID in two patients with Sweet's syndrome, but neither responded.[34]

References