Sweet syndrome associated with furosemide.

Abstract: This case report describes a case of Sweet syndrome (SS) related to use of furosemide in a 46-year-old female who was admitted for treatment of congestive heart failure. Three days after administration of furosemide, the patient had a fever and a skin eruption appeared on her wrists, forearms, and legs. Biopsy of the skin lesion was consistent with SS. Infection was thought to be unlikely because of negative blood cultures, echocardiography, and other imaging studies. Careful review of her medications revealed that the patient received furosemide before the appearance of the skin eruption and fever. After discontinuation of furosemide, the patient's skin lesion and fever resolved. A MEDLINE search from June 1966 to May 2004 revealed only one reference documenting the association of SS with furosemide administration. Patients who have development of SS without an obvious cause should have their medication list closely reviewed.

Key Words: acute neutrophilic dermatosis, drug-induced Sweet syndrome, Sweet syndrome

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Sweet syndrome (SS) is the prototype of neutrophilic dermatosis. The disorder is characterized by acute onset of fever, leukocytosis, and erythematous plaques. Histopathology of the skin lesions show infiltrating neutrophils, primarily in the dermis. SS is associated with a variety of disorders, including malignancies, autoimmune disorders, respiratory tract infections, and, infrequently, with medications. We present a case of SS, with associated iritis, secondary to furosemide administration.

Case Report

A 46-year-old female was admitted with congestive heart failure secondary to aortic stenosis. She was started on intravenous furosemide. Three days later, the patient had a low-grade fever and soon thereafter was noted to have tender, papular, erythematous, nonpruritic skin eruptions bilaterally in the wrists, forearms, arms, and thighs (Figs. 1 and 2). There was redness in both eyes and associated photophobia. Investigation for an infectious cause of the fever and rash revealed negative blood culture, urine culture, sputum culture, chest radiography, and echocardiogram. A biopsy of a skin lesion on the left arm revealed a superficial dermal nodular neutrophilic infiltrate associated with nuclear dust and rare eosinophils, consistent with SS (Figs. 3 and 4). The patient's eye symptoms were thought to be consistent with episcleritis and iritis. Furosemide was discontinued, and the skin lesions and eye symptoms gradually subsided.

Discussion

Sweet syndrome was first described in 1964 in eight female patients. (1) The disorder was characterized by the acute onset of fever, leukocytosis, and erythematous plaques, with histology of infiltrating neutrophils, primarily in the dermis. Originally this entity was termed acute febrile neutrophilic dermatosis, which subsequently was renamed Sweet syndrome. Neutrophilic dermatoses are characterized by skin lesions with an intense epidermal and/or dermal inflammatory infiltrate of neutrophils without evidence of infection or vasculitis. SS can manifest as a spectrum of skin lesions including vesiculopustules, plaques, nodules, and ulcerations in the same patient. The dermatoses can be localized or widespread and rarely have extracutaneous involvement of lymph nodes, spleen, bones, liver, or lung.

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The pathogenesis of SS is not clearly understood. The current hypothesis suggests the disorder is related to altered immunologic reactivity. Consistent with this hypothesis is the observation that these disorders generally respond to anti-inflammatory and immunomodulatory therapy. Cytokine dysregulation could account for most of the clinical, pathologic, and laboratory changes seen in SS. Among the potentially involved cytokines are the interleukins (IL-1, IL-3, IL-6, and IL-8), granulocyte colony-stimulating factor, granulocyte-macrophage colony stimulating factor, and interferon-[gamma]. (2,3)

SS has been associated with infections, autoimmune diseases, inflammatory bowel disease, malignancy, and drugs, suggesting a hypersensitivity reaction. (4-14) The onset of skin and eye lesions in our patient was preceded by administration of furosemide, which quickly resolved after discontinuation of the drug. Sweet (1) initially described four main features of acute febrile neutrophilic dermatosis: (1) fever, (2) peripheral neutrophilic leukocytosis, (3) abrupt onset of raised, often painful plaques on the limbs, face, and neck, and (4) dense dermal neutrophilic infiltrates without vasculitis.

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In 1986, Su and Liu (15) proposed another set of criteria for the diagnosis of SS. According to this schema, major criteria include (1) abrupt onset of tender or painful erythematous or violaceous plaques or nodules and (2) predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis. Minor criteria, according to this classification, include (1) preceding fever or evidence of infection, (2) fever, arthralgia, conjunctivitis, or underlying malignancy, (3) leukocytosis, and (4) a favorable therapeutic response to systemic steroids and not to antibiotics. Diagnosis of SS is dependent on fulfilling both of the major criteria and at least two of the minor criteria.

In 1996, Walker and Cohen (16) described criteria for drug-induced SS. These criteria include (1) abrupt onset of painful erythematous plaques or nodules, (2) histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, (3) pyrexia greater than 38[degrees]C, (4) temporal relation between the drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge, and (5) temporally related resolution of lesions after drug withdrawal or treatment with systemic steroids.

The average duration from the administration of drug to the onset of skin lesions was found to be approximately 5 to 7 days (11) in most cases.

Our patient fulfilled the criteria for diagnosis of drug-induced SS. To our knowledge, only one reported case of SS associated with furosemide has been described in the English literature. Our patient was unique in that she also had symptoms and clinical findings suggestive of iritis, which is an uncommon eye finding in SS. (8,17)

Conclusion

Sweet syndrome is a rare skin disorder, associated with various medical conditions and drugs. In patients in whom no obvious cause for SS can be found, a careful review of their drug history is essential. Withdrawal of the offending drug results in disappearance of the skin lesions.

Accepted November 22, 2004.

References

1. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964;74:349-356.

2. Reuss-Borst MA, Pawelec G, Saal JG, et al. Sweet's syndrome associated with myelodysplasia: possible role of cytokines in the pathogenesis of the disease. Br J Haematol 1993;84:356-358.

3. Reuss-Borst MA, Muller CA, Waller HD. The possible role of G-CSF in the pathogenesis of Sweet's syndrome. Leuk Lymphoma 1994;15:261-264.

4. Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders: atypical forms of pyoderma gangrenosum and Sweet's syndrome associated with myeloproliferative disorders. J Am Acad Dermatol 1983;9:751-758.

5. Soppi E, Nousiainen T, Seppa A, et al. Acute febrile neutrophilic dermatosis (Sweet's syndrome) in association with myelodysplastic syndrome: a report of three cases and a review of the literature. Br J Haematol 1989;73:43-47.

6. Apted JH. Sweet's syndrome (acute febrile neutrophilic dermatosis) associated with multiple myeloma. Australas J Dermatol 1984;25:15-17.

7. Saxe N, Gordon W. Acute febrile neutrophilic dermatosis (Sweet's syndrome): four case reports. S Afr Med J 1978;53:253-256.

8. Gunawardena DA, Gunawardena KA, Ratnayaka RMRS, et al. The clinical spectrum of Sweet's syndrome (acute febrile neutrophilic dermatosis): a report of eighteen cases. Br J Dermatol 1975;92:363-373.

9. Fye KH, Crowley E. Berger TG, et al. Celecoxib-induced Sweet's syndrome. J Am Acad Dermatol 2001;45:300-302.

10. Sequeira W, Polisky RB, Alrenga DP. Neutrophilic dermatosis (Sweet's syndrome): association with a hydralazine-induced lupus syndrome. Am J Med 1986;81:558-560.

11. Paydas S, Sahin B, Seyrek E, et al. Sweet's syndrome associated with G-CSF. Br J Haematol 1993;85:191-192.

12. Cobb MW. Furosemide-induced eruption simulating Sweet's syndrome. J Am Acad Dermatol 1989;21:339-343.

13. Veres K, Haraszti A, Nemes Z, et al. Sweet syndrome following therapeutic use of granulocyte colony stimulating factor. Orvosi Hetil 1999;140:1059-1061.

14. Arbetter KR, Hubbard KW, Markovic SN, et al. Case of granulocyte colony-stimulating factor-induced Sweet's syndrome. Am J Hematol 1999;61:126-129.

15. Su WP, Liu HN. Diagnostic criteria for Sweet's syndrome. Cutis 1986;37:167-174.

16. Walker DC, Cohen PR. Trimethoprim-sulphamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome. J Am Acad Dermatol 1996;34:918-923.

17. Nicolaides MR, Packles PJ, Schutzer PJ. Iritis associated with Sweet's syndrome. Clin Exp Dermatol 2000;25:349-354.

RELATED ARTICLE: Key Points

* Sweet syndrome is the prototype of acute neutrophilic dermatosis.

* The pathogenesis of Sweet syndrome remains unknown; cytokine dysregulation could account for most of the clinical, pathologic, and laboratory changes seen in Sweet syndrome.

* Sweet syndrome can be associated with infections, malignancies, autoimmune disorders, and drugs.

* The medical literature has established criteria for the diagnosis of Sweet syndrome including that secondary to drug administration.

* Careful review of a patient's medication usage is required in a patient who has development of Sweet syndrome without obvious cause.

Gurushankar Govindarajan, MD, Qaiser Bashir, MD, Saravanan Kuppuswamy, MD, and Charles Brooks, MD

From the University of Missouri Health Science Center, Department of Internal Medicine, Columbia, MO.

Reprint requests to Dr. Gurushankar Govindarajan, University of Missouri Health Science Center, Department of Internal Medicine, MA 406, One Hospital Drive, Columbia, MO 65212. Email: [e-mail]