A 71-year-old Caucasian man with myelodysplastic syndrome and on chemotherapy with azacitidine presented to the hospital with 2 days of high fever and 4 days of worsening skin lesions. The lesions appeared on the elbows as “blood blisters,” which grew larger and more painful. He denied any other new medications. He was placed on broad spectrum antibiotics by infectious disease physicians out of concern for ecthyma gangrenosum, and dermatology was consulted. On examination, violaceous, edematous plaques with a central pseudovesicle were seen on the bilateral elbows. Punch biopsies were performed for tissue culture and histology.
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Sweet syndrome (SS) is a dermatologic disorder with clinical and histologic features that can be associated with several systemic disorders and medications.1 It was first reported in 1964 by Robert Sweet, who described ‘an acute febrile dermatosis’ he witnessed in 8 middle-aged women.2 The patients he described had skin eruptions that resembled erythema multiforme, fever, and polymorphonuclear leukocytosis. In general, SS presents with characteristic skin findings of painful erythematous plaques, nodules, or papules, as well as prodromal symptoms such as malaise, fever, and arthalgias.3
SS can be classified into three groups: idiopathic or classical, drug-induced, and malignancy-associated, each of which may have unique aspects of presentation. Classical SS generally affects women aged 30 to 50 years and may be associated with infection, pregnancy, or autoimmune diseases such as inflammatory bowel disease.1 Many drugs have been implicated in causing SS, with granulocyte colony-stimulating factor considered one of the most common.3 Other implicated medications include antibiotics, antiepileptic drugs, anti-HIV drugs, antihypertensives, antineoplastics, antipsychotics, antithyroid hormone synthesis drugs, contraceptives, diuretics, nonsteroidal anti-inflammatory agents, and retinoids.1
As seen in our patient with myelodysplastic syndrome (MDS), the onset of SS can herald, follow, or appear simultaneously with the diagnosis of a patient’s neoplasm.1 About one-fifth of patients with SS have an associated malignancy, most commonly hematologic disease.4 SS is often associated with MDS, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and solid tumors. A recent study showed that malignancy-associated SS is associated with the histiocytoid or subcutaneous subtype, lack of arthralgia, and cytopenias, including leukopenia, thrombocytopenia, and anemia.5 Men and women with malignancy-associated SS have lower hemoglobin levels, compared with other variations of SS. In addition, malignancy-associated SS affects older patients than other classifications of SS.3 Monitoring for flares of SS is important, as these may represent recurrence of the underlying disease and can be the first sign.4
The differential diagnosis for SS is vast, as SS may resemble several conditions clinically and histologically. The differential for SS includes drug eruptions; infectious and inflammatory disorders such as bacterial sepsis, cellulitis, erysipelas, and panniculitis; neoplastic conditions such as leukemia cutis; reactive erythemas such as erythema multiforme and erythema nodosum; and vasculitis such as leukocytoclastic vasculitis and periarteritis nodosa.1
On histology, SS is characterized by neutrophillic infiltration located in the upper dermis. However, a variant with neutrophils and histiocytes in the dermis exists, known as histiocytoid SS, and is more commonly associated with MDS and malignancy than the classical neutrophilic variant.5,6 Kulasekararaj et al described 15 patients with SS who had ‘immune dysregulation’ secondary to MDS. On biopsy, the prominent findings included mild spongiosis of the epidermis, intense neutrophilic infiltrate in the reticular dermis, leukocytoclasis, lymphocytes and histiocytes in the infiltrate, and dilatation of blood vessels with endothelial swelling. The diagnosis of chronic relapsing SS can be delayed because the pathology is not always representative of classical neutrophil-rich SS and instead contains lymphocytic and histiocytoid infiltrates.7
Although it is regarded to be beneficial to treat underlying malignancy and stop any offending drug agent, in certain cases of SS, the treatment for SS and its corresponding efficacy is remarkably similar regardless of classification.1,3,6 Most patients have a complete response to therapy. Systemic steroids are the most commonly administered agent and considered first-line.6 Second-line therapies include dapsone, colchicine, and systemic agents such as cyclosporine, azathioprine, etanercept, thalidomide, and anakinra.3 However, relapse of SS is common upon corticosteroid reduction in those patients with MDS.8 Relapsing-remitting SS is a harbinger of myelodysplastic syndrome, and chronic relapsing-remitting of SS can be recalcitrant to treatment. Kulasekararaj et al demonstrated that most patients in their study with MDS and SS had to be maintained on a higher doses of steroids and that the response to immunosuppressive therapy is variable.7 Corticosteroids were effective in all patients; yet lower doses of prednisolone (lower than 15 mg) usually resulted in relapse of SS.
Cases of azacitidine-associated SS have been reported in the literature.9 However, some patients with MDS may achieve clinical remission of refractory SS while being on azacytidine, making the drug’s role in SS unclear.10,11
The patient was treated with systemic steroids and colchicine; however, the patient relapsed several times, particularly following blood transfusions. He later passed away from complications of his underlying condition.
Margaret Barton is a 4th year medical student at Virginia Commonwealth University in Richmond, and Jessica Boulavsky, MD, is a dermatology resident at the Baylor College of Medicine in Houston.
- Cohen PR. Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34.
- Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;76:349-356.
- Rochet MN, Chavan RN, Wada DA, Gibson LE. Sweet syndrome: clinical presentation, associations, and response to treatment in 77 patients. J Am Acad Dermatol. 2013;69:557-564.
- Raza S, Kirkland R, Patel A, et al. Insight into Sweet’s syndrome and associated-malignancy: a review of the current literature. Int J Oncol. 2013;42:1516-1522.
- Nelson CA, Noe MH, McMahon CM, et al. Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center. J Am Acad Dermatol. 2018;78:303-309.
- Ghoufi L, Ortonne N, Ingen-Housz-Oro S, et al. Histoid Sweet syndrome is more frequently associated with myelodysplastic syndromes than the classical neutrophilic variant: a comparative series of 62 patients. Medicine (Baltimore). 2016;95:e3033.
- Kulasekararaj AG, Kordasti S, Basu T et al. Chronic relapsing remitting Sweet syndrome—a harbinger of myelodysplastic syndrome. Br J Haematol. 2015;170:649-656.
- Wang Y, Zhuang JL, Zhao WL, et al. Clinical analysis of Sweet syndrome with myelodysplastic syndrome. Zhongua Yi Xue Za Zhi. 2016;96:1755-1757.
- Bonazza S, Dalton B, Hardin J, Metelitsa A. Histiocytoid variant of Sweet syndrome associated with azacitidine recurrence upon rechallenge. Can J Hosp Pharm. 2015;68: 339-341.
- Lin C, Yeh S, Tin T. Azacitidine is effective for the treatment of myelodysplastic syndrome and accompanied Sweet syndrome. Ann Hematol. 2015;94:1925-1926.
- Martinelli S, Rigolin G, Leo G, et al. Complete remission of Sweet’s syndrome after azacytidine treatment for concomitant myelodysplastic syndrome. Int J Hematol. 2014; 99:663-667.