BASICS
DESCRIPTION
- An uncommon inflammatory disorder of the skin that is characterized by the abrupt onset of painful, edematous, and erythematous lesions (papules, plaques, or nodules) (1). The lesions are often accompanied by fever and leukocytosis.
- Histologically characterized by diffuse dermal infiltration of mature neutrophils, leukocytoclasis, papillary dermal edema, and an absence of vascular infiltration (vasculitis)
- Classified into three main subtypes
- Classic (idiopathic): majority of cases; often follows 1 to 3 weeks after an upper respiratory tract/GI infection; also associated with inflammatory bowel disease (Crohn disease and ulcerative colitis) and pregnancy
- Malignancy-associated: may precede, appear simultaneously, or follow a hematologic malignancy or a solid tumor; more commonly associated with hematologic malignancies, most commonly acute myelogenous leukemia
- Drug-induced: Multiple drugs have been implicated including cytokines, antiepileptics, antipsychotics, anti-inflammatory drugs (celecoxib, diclofenac), antihypertensives, antimicrobials (minocycline, ofloxacin, nitrofurantoin, trimethoprim-sulfamethoxazole), immunosuppressives, antineoplastics, retinoids, and oral contraceptives (levonorgestrel/ethinyl estradiol). The cytokine, G-CSF is most frequently reported. Usually occurs ~2 weeks following drug exposure, with recurrence when reexposed to the drug.
- Extracutaneous manifestations of the disease have been reported in almost every organ system.
- Synonym: acute febrile neutrophilic dermatosis
EPIDEMIOLOGY
- Manifests at any age, classic peaks at 30 to 60 years of age
- Often based on subtype
- Classic: 80% are women; 75 " 90% have a prior upper respiratory infection (URI); 30% recurrence
- Drug-induced: 71% are women; 67% recurrence
- Malignancy-associated: underlying hematologic malignancy: 50% are women; underlying solid tumor: 59% are women.
- There is no racial predilection.
ETIOLOGY AND PATHOPHYSIOLOGY
- Pathogenesis is multifactorial. Theorized factors include hypersensitivity reactions, cytokine dysregulation, and infection.
- This may include an imbalance and dysregulation of neutrophils and T1 helper cells with a hypersensitivity reaction to bacterial, viral, or tumor antigen; or the effect of cytokines, specifically G-CSF, GM-CSF.
Genetics
Abnormalities in chromosome 3q. In Japanese patients, HLA B-54 has been linked.
RISK FACTORS
Female sex, upper respiratory tract infection, pregnancy, hematologic malignancy, myelodysplastic syndrome, solid neoplasias, medications (antiepileptics, oral contraceptives, antimicrobials, antihypertensives, immunosuppressives, antineoplastics, anti-inflammatories), inflammatory conditions (inflammatory bowel disease [IBD], autoimmune diseases)
COMMONLY ASSOCIATED CONDITIONS
- Upper respiratory/GI infection
- IBD (both Crohn disease and ulcerative colitis)
- Pregnancy
- Neutrophilic dermatoses, including erythema elevatum diutinum, neutrophilic eccrine hidradenitis, and pyoderma gangrenosum
- Hematologic cancers, most frequently associated with acute myelocytic leukemia and acute promyelocytic leukemia
- May occur in settings of patients with hematologic disorders
- Paraneoplastic syndrome
- Drug-induced dermatosis secondary to all-trans retinoic acid, G-CSF, and imatinib
- Simultaneously with leukemia cutis
DIAGNOSIS
HISTORY
- The most frequent symptom is fever, which may precede the cutaneous manifestations by several days to weeks and can be present throughout the entire episode.
- Patients may report an antecedent URI or influenza-like illness 1 to 3 weeks prior to skin lesions.
- Abrupt onset of tender, edematous, erythematous lesions
- Arthralgia, general malaise, headache, and myalgia may also be present.
PHYSICAL EXAM
- Fever
- Skin lesions are reddish, blue, or violet papules, plaques, and nodules. They are asymmetric in distribution, most commonly found on the upper extremities, head, and neck. Lesions may be found on the lower extremities in cases of drug-induced or malignancy-associated subtypes but rarely in the classic subtype. The lesions may appear transparent (vesicle or bullous-like, likely secondary to dermal edema) but are typically solid. Lesions vary from millimeters to several centimeters in diameter.
- Extracutaneous manifestations
- Eyes: most common; erythematosus conjunctival lesions, conjunctivitis, iritis, episcleritis
- Musculoskeletal: generalized arthralgias and myalgias
- Ears: pustules of the external auditory canal and tympanic membrane
- Heart: aortic stenosis, cardiomegaly
- Lung: pleural effusion (fluid shows abundant neutrophils without microorganisms)
- Oral mucosa: more commonly related to hematologic malignancies; ulcers of the buccal mucosa and palate, bullae and vesicles, gingival hyperplasia, tongue swelling
- Bone: sterile osteomyelitis reported in children
- Spleen: splenomegaly
DIFFERENTIAL DIAGNOSIS
- Clinical cutaneous differentials
- Acral erythema, drug eruptions, halogenoderma, and rosacea fulminans. Those that are infectious and/or inflammatory disorders include bacterial sepsis, cellulitis, erysipelas, herpes simplex virus (HSV), leprosy, lymphangitis, panniculitis, pyoderma gangrenosum, syphilis, systemic mycoses, thrombophlebitis, tuberculosis, and viral exanthems.
- Neoplasias include chloroma, leukemia cutis, lymphoma, and metastatic tumor(s). Systemic diseases include Beh งet disease, bowel bypass syndrome, dermatomyositis, familial Mediterranean fever, and lupus erythematosus. Vasculitis includes erythema elevatum diutinum, granuloma faciale, leukocytoclastic vasculitis, and periarteritis nodosa.
- Histologic differentials
- Abscess/cellulitis, bowel bypass syndrome, erythema elevatum diutinum, granuloma faciale, halogenoderma, neutrophilic eccrine hidradenitis, pyoderma gangrenosum, and rheumatoid neutrophilic dermatitis
- Leukemia cutis can occur simultaneously; however, the dermal infiltrate of leukemia consists of malignant immature leukocytes.
- Documented variant may include a deep mycotic infection.
DIAGNOSTIC TESTS & INTERPRETATION
- Diagnostic criteria have been divided into major and minor. Must have two major and four minor criteria met
- Major
- Rapid onset of characteristic skin lesions (tender erythematosus plaques and/or nodules)
- Typical histopathologic features: dense neutrophil infiltration without vascular infiltrate
- Minor
- Fever (>38 ฐC)
- History of URI/GI infection or immunization, the presence of hematologic/solid neoplasia, inflammatory disorder, or pregnancy
- Dramatic response to corticosteroid, potassium iodide, or colchicine
- 3 of 4 of the following labs
- Erythrocyte sedimentation rate (ESR) >20 mm/hr
- + C-reactive protein (CRP)
- WBC >8 109/L
- Neutrophils >70%
Initial Tests (lab, imaging)
- CBC with leukocyte differential and platelet count
- Often shows a peripheral leukocytosis with neutrophilia. However, neutrophilia is not required and neutropenia has been described in some cases.
- Elevated ESR and CRP
- Serum chemistries for the evaluation of hepatic and renal function
- Where clinically appropriate, consider MRI: Look for myositis, fasciitis of the muscles.
- Where clinically appropriate, single-photon emission computed tomography (SPECT) scan of the brain
Follow-Up Tests & Special Considerations
- Extracutaneous manifestations, which have been reported in almost every organ system, may result in multiple lab abnormalities.
- Hematuria and proteinuria may be seen with renal involvement and liver enzyme elevation with liver involvement.
- Systemic inflammatory response syndrome (SIRS) can be an extracutaneous manifestation of Sweet syndrome and should be considered when a patient meets SIRS criteria, has a negative infectious workup, fails to respond to broad-spectrum antimicrobials, and improves with initiation of systemic corticosteroid therapy (2).
Diagnostic Procedures/Other
- Lesional skin biopsy for routine histopathologic evaluation to confirm suspected diagnosis
- Bacterial, fungal, mycobacterial, and possibly, viral cultures of lesions to discover infectious etiology
Test Interpretation
Characteristically involves the dermis. There is a diffuse infiltrate of mature neutrophils along with edema within the superficial dermis. The overlying epidermis is normal with an absence of leukocytoclastic vasculitis (fibrin deposition/neutrophils with the vessel walls). The subcutaneous tissue is typically spared. The presence of subcutaneous neutrophilic inflammation suggests an underlying malignancy, more commonly hematologic in nature and less commonly a solid tumor.
TREATMENT
If untreated, can remain for weeks to months. Without therapeutic intervention, the cutaneous lesions and dermatosis-related symptoms eventually resolve in cases of the classic subtype. In cases of malignancy-associated subtype, occasionally resolution of Sweet syndrome will follow cure/remission of the dermatosis-related cancer. In drug-induced subtype, spontaneous improvement and clearing may occur after stopping the inciting medication.
MEDICATION
- Topical corticosteroids or intralesional injection of corticosteroids can be used if lesions are minimal in number and localized to a small area. High-potency topical corticosteroids, in either cream, ointment, or gel/foam base, can be applied to each cutaneous lesion.
- Intralesional injections with triamcinolone acetonide 3 to 10 mg/mL
First Line
- Systemic corticosteroids
- Prednisone 1 mg/kg/day PO. Taper dose over 4 to 6 weeks after disease control. Some may require 2 to 3 months of treatment of therapy; use lowest effective dose (generally 10 to 20 mg/day) (3)[B].
- Methylprednisolone sodium succinate IV administration up to 1,000 mg/day over ≥1 hour, daily for 3 to 5 days may be needed in severe cases, followed by a tapering dose of an oral corticosteroid/other immunosuppressant agent (3)[B].
- Potassium iodide administered PO as 300 mg enteric-coated tablets, TID (3)[B]
- Colchicine administered PO at a dose of 0.6 mg TID (3)[B]
Second Line
All of these agents have been used as monotherapy initially or after first-line therapies have failed.
- Indomethacin 150 mg/day PO for 7 days, followed by 100 mg/day PO for 14 days (3)[B]
- Initiate dapsone with 25 mg/day; increase as tolerated up to 100 to 200 mg/day (3)[B]
ADDITIONAL THERAPIES
Clofazimine (not available in United States), cyclosporine, methotrexate (3)[B]
- Antibiotic agents
- Metronidazole in patients with IBD
- Doxycycline, minocycline, or tetracycline in dermatosis-related Yersinia or Chlamydia infections
- Appropriate antimicrobial agent to which Staphylococcus aureus is susceptible in cases of lesions that become secondarily impetiginized by Staphylococcus infection
SURGERY/OTHER PROCEDURES
Surgical intervention (tonsillectomy, tumor resection, nephrectomy) has occasionally promoted resolution if the dermatosis was associated with tonsillitis, solid tumors, or renal failure.
ONGOING CARE
PROGNOSIS
- In the classic subtype, symptoms may remit or show resolution without therapeutic intervention.
- Successful management of the cancer in the malignancy-associated subtype occasionally results in clearing.
- Spontaneous improvement and resolution will follow discontinuation of the inciting medication in the drug-induced subtype.
- The duration of remission between episodes varies. Recurrences are more common in cancer patients and may represent return of a previously treated malignancy.
- Recurrence in up to 50% (more common with hematologic malignancy or drug-related cases)
COMPLICATIONS
- Ulcerative skin lesions, oral lesions, abnormal platelet counts, and/or anemia associated with Sweet syndrome should prompt a thorough search for an underlying malignancy.
- Complicated cases require multidisciplinary care in consultation with dermatology, rheumatology, and other subspecialists.
REFERENCES
11 Cohen PR. Sweet 's syndrome " a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34.22 Vanourny J, Swick BL. Sweet syndrome with systemic inflammatory response syndrome. Arch Dermatol. 2012;148(8):969 " 970.33 Cohen PR, Kurzrock R. Sweet 's syndrome: a review of current treatment options. Am J Clin Dermatol. 2002;3(2):117 " 131.
ADDITIONAL READING
- Chan MP, Duncan LM, Nazarian RM. Subcutaneous Sweet syndrome in the setting of myeloid disorders: a case series and review of the literature. J Am Acad Dermatol. 2013;68(6):1006 " 1015.
- Park CW, Kim YJ, Seo HJ, et al. A case of Sweet 's syndrome in a patient with liver cirrhosis caused by chronic hepatitis B. Korean J Gastroenterol. 2012;59(6):441 " 444.
- Paydas S. Sweet 's syndrome: a revisit for hematologists and oncologists. Crit Rev Oncol Hematol. 2013;86(1):85 " 95.
CODES
ICD10
L98.2 Febrile neutrophilic dermatosis [Sweet]
ICD9
695.89 Other specified erythematous conditions
SNOMED
- Acute febrile neutrophilic dermatosis (disorder)
- Sweet 's disease following infection (disorder)
- Sweet 's disease due to drug (disorder)
CLINICAL PEARLS
- Consider Sweet syndrome in patients with abrupt onset of fever and asymmetric, erythematous, tender papules, plaques, or nodules.
- Skin biopsy is diagnostic.