Background
Acute febrile neutrophilic dermatosis was first described by Robert Douglas Sweet in 1964 (hence the eponym Sweet syndrome). This condition is a reactive process characterized by the abrupt onset of tender, red-to-purple papules and nodules that coalesce to form plaques. These plaques usually occur on the upper extremities, face, or neck and are typically accompanied by fever and peripheral neutrophilia. [1, 2] Sweet syndrome can be divided into three types on the basis of the underlying trigger. [3]
The first and most common type is classic or idiopathic Sweet syndrome, which occurs predominantly in young women after a mild respiratory illness and may be linked to pregnancy, inflammatory bowel disease (IBD), [3, 4] vaccinations, other inflammatory disorders, and infections. [5]
The second type can manifest aggressively in concert with an underlying malignancy. In some reports, the lesions of Sweet syndrome are the first clue to an underlying malignancy. [6] It is important to note that cutaneous lesions can also occur in the context of an established neoplastic process, as well as a paraneoplastic syndrome. [3] Acute myelogenous leukemia (AML) is the most common neoplasm with which malignancy-associated Sweet syndrome occurs, [7, 8, 9] along with myelodysplastic syndrome (MDS). [5]
The third type is an iatrogenic form that is recognized on the basis of reports of a variety of therapies bringing about lesions. The agents most commonly implicated are those that increase granulocyte colony-simulating factor (G-CSF). [10, 11, 12, 13] Other agents that have caused this variant of Sweet syndrome include trimethoprim-sulfamethoxazole, [14] minocycline, levonorgestrel/ethinyl estradiol, and all-trans retinoic acid (ATRA; or tretinoin). In addition, multiple antineoplastic agents, biologic agents, [5] and radiotherapy [15] have been implicated in the onset of these lesions.
In general, Sweet syndrome responds well to oral corticosteroids. If untreated, however, it may persist for weeks or months and usually improves without scarring. [3] Recurrence has been reported mainly in idiopathic and malignancy-related Sweet syndrome. [3] In rare cases, crops of lesions recur and can persist indefinitely. [2] Cases associated with malignancy can present with bullous or ulcerative lesions, which can resemble atypical pyoderma gangrenosum. These lesions are often recalcitrant to treatment. [2, 10, 16, 17]
The diagnosis of Sweet syndrome is based on fulfillment of both clinical and histopathologic criteria. Characteristics that distinguish the lesions of Sweet syndrome from other neutrophilic dermatoses are (1) healing of the lesions without scarring and (2) absence of vasculitis on histopathologic examination.
Pathophysiology
Acute febrile neutrophilic dermatosis is a hypersensitivity reaction that occurs in response to systemic factors, such as hematologic disease, infection, inflammation, vaccination, or drug exposure. [2] The condition is neutrophil-mediated, as evidenced by its histopathologic appearance, associated neutrophilia, and response to medications that affect neutrophil activity. [2]
The association of exogenous G-CSF with the development of Sweet syndrome also supports the impact of neutrophils and related endogenous cytokines in the underlying process. [10, 12] G-CSF suppresses apoptosis and prolongs neutrophil survival in vivo in a CD34+ cell population. G-CSF levels are increased in the peripheral blood of patients with active Sweet syndrome, suggesting that high levels of G-CSF may correlate with the activity of disease. [11]
The functional properties of neutrophils, rather than the absolute number, is thought to be significant, in that patients with Sweet syndrome due to G-CSF develop lesions as the neutrophil count rapidly increases, despite a decreased absolute neutrophil count. [17] (See the Absolute Neutrophil Count calculator.) In addition to G-CSF, the use of ATRA in the context of acute promyelocytic leukemia has shown the propagation of aberrant neutrophils as seen in drug-induced Sweet syndrome. [18]
Some studies have suggested a role for cytokines such as interleukin (IL)-1, IL-2, and interferon gamma (IFN-γ) in concert with type 1 helper T (Th1) cells, which may contribute to the pathogenesis of Sweet syndrome. [19] This is especially apparent with the malignancy-related form of the syndrome, in which patients who are given G-CSF, IFN-γ, and ATRA develop the characteristic lesions. [20] Studies have observed increased IL-6 with increasing disease activity and concomitant decrease in IL-6 after corticosteroids are used. [21, 22]
A possible genetic link with human leukocyte antigen (HLA)-B54 has been observed in the Japanese population. [23] A report of two brothers who developed Sweet syndrome in the neonatal period also supported a genetic predisposition. [24] Structural alterations in the long arm of chromosome 3 (3q) have been seen in association with Sweet syndrome; these changes involve genes that affect the regulation of granulopoiesis and neutrophil migration. [24]
Another genetic link is HLA-Cw1, which has been observed in neurologic Sweet syndrome. [23, 25] In addition, mutations in fms-like tyrosine kinase-3 have been associated with Sweet syndrome‒like skin disease, which has presented with mutated progenitors of neutrophils. [26, 27]
Etiology
Potential causes of Sweet syndrome (acute febrile neutrophilic dermatosis) are numerous and depend on the type. In one case series of 176 patients, classic or idiopathic Sweet syndrome was the most common presentation and accounted for more than 71% of cases; Sweet syndrome associated with malignancy or an underlying condition (eg, infection or inflammatory disease) accounted for approximately 27% of the cases. [28]
Most of the underlying malignancies reported in the literature have been hematopoietic (most commonly AML), [7, 8, 28] but some have been due to solid tumors, mostly involving the genitourinary (GU) tract, breast, and gastrointestinal (GI) tract. [6] Finally, approximately 2% of cases overall have been associated with pregnancy. [29, 28, 30]
Hematologic malignancies
Several myeloid hematologic malignancies have been associated with Sweet syndrome, including myelodysplasia, [7] chronic myelogenous leukemia (CML), [31] and AML, including the promyelocytic (M3) variant of AML. [8]
Other nonmyeloid hematologic malignancies reported to occur in conjunction with Sweet syndrome include mycosis fungoides, Hodgkin disease, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, hairy cell leukemia, and multiple myeloma; patients with immunoglobulin G (IgG) secretion may be at increased risk for Sweet syndrome. [32, 33, 34]
Nonhematologic malignancies
These rare associations include osteosarcoma, oral or tonsil cancer, ovarian cancer, thyroid cancer, lung cancer, pheochromocytoma, and cervical and rectal carcinoma. [17, 34, 35]
GU, breast, and GI cancers have also been reported in patients with Sweet syndrome. [7]
Infections
Multiple infections have been associated with Sweet syndrome, often involving the upper respiratory tract. Streptococcal pneumonia is the most commonly implicated infection. [36]
Other bacteria that can lead to Sweet syndrome include Salmonella species, Staphylococcus species, Francisella tularensis, Yersinia enterocolitica, Entamoeba coli, Helicobacter pylori, Borrelia burgdorferi, tuberculous mycobacteria, Mycobacterium chelonae, and Penicillium species. [36, 37, 38] Yersinia-associated Sweet syndrome has been noted to improve with antibiotics. [39]
Fungal infections have also been linked to the onset of Sweet syndrome; the syndrome may be a presenting feature of coccidiomycosis and has been associated with sporotrichosis. [40, 41] Viral agents such as HIV, cytomegalovirus (CMV), hepatitis A virus (HAV), hepatitis B virus (HBV), and parvovirus B19 have also been implicated. [42, 43]
Iatrogenic factors
Because the dominant cell in the dermal infiltrate of Sweet syndrome is the neutrophil, drug-induced Sweet syndrome is not considered to be a drug hypersensitivity. G-CSF is a well-established factor [2] ; other established factors include trimethoprim-sulfamethoxazole, ATRA, and minocycline, all of which have appeared in more than one case report. [14] It should be noted that multiple reports detailing drugs as causes of Sweet syndrome have involved patients with underlying malignancy; therefore, the specific causal link between drugs and Sweet syndrome is still unclear. [2] Anecdotal or limited reports of drug or device associations have included the following:
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Lithium
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Furosemide
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Hydralazine
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Carbamazepine
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Oral contraceptives
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Mirena intrauterine device [44]
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COX-2 inhibitors [45]
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Azathioprine [46]
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Doxycycline
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Diazepam
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Diclofenac
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Nitrofurantoin
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Propylthiouracil
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Lenalidomide [47]
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Bortezomib [48]
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Abacavir
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Imatinib
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Azacitidine [49]
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Decitabine [50]
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IL-2 [51]
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Clindamycin [52]
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Mitoxantrone [53]
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Ticagrelor [56]
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Dapagliflozin [57]
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Erlotinib [58]
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Tocilizumab [59]
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Dabrafenib and trametinib [62]
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Mesalamine [63]
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Ibrutinib [64]
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Ipilimumab [65]
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Fluconazole [66]
A more complete list of drugs reported to be associated with Sweet syndrome can be found in a review by Nelson et al, though not all of these agents were explicitly described as causing drug-induced Sweet syndrome. [5]
Systemic disorders
Associated inflammatory disease can be identified in about 16% of patients with Sweet syndrome. [28] The most common inflammatory conditions are Crohn disease and ulcerative colitis, which some authors consider part of a continuum of neutrophilic dermatosis. [67]
Sjögren syndrome, Behçet disease, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, and undifferentiated connective-tissue disease have also been reported in association with Sweet syndrome. [2, 68]
Miscellaneous causes
Rare cases of Sweet syndrome have occurred with spinal surgery, sarcoidosis, erythema nodosum, relapsing polychondritis, thyroiditis, and systemic lupus erythematosus (SLE). [2, 69, 70, 71, 72]
About 2% of cases have been reported in the context of pregnancy. [2, 29, 30, 73]
Several cases of Sweet syndrome have occurred with polycythemia vera. [74]
One patient had a mutation in the prothrombin gene (G20210A), but no conclusive association has been established. [75]
A few cases of Sweet syndrome have been reported in transplant patients, including those undergoing bone marrow and kidney transplantation. Although these patients are taking immunomodulatory medications, an immune-mediated state has been described to explain the manifestation of Sweet syndrome in this patient population. [76]
Sweet syndrome as a manifestation of HIV-associated immune reconstitution inflammatory syndrome has been suggested. [77]
There have also been multiple reports of Sweet syndrome induced by radiotherapy. [15, 78, 79, 80]
Epidemiology
US and international statistics
Sweet syndrome (acute febrile neutrophilic dermatosis) has been listed as a rare disease by the National Organization for Rare Disorders (NORD), [81] with only a few hundred cases in the literature (~80 in children), but it is possible that it is underreported and thus may be better described as uncommon. [82] In several series, 10-20% of cases have occurred in a setting of malignancy, though most are idiopathic or associated with benign conditions. [14, 16]
Age-, sex-, and race-related demographics
Typically, women with Sweet syndrome are between the ages of 30 and 50 years. [2] However, cases in neonates as young as 5 days have been described. [83] In children, Sweet syndrome is extremely rare and is generally associated with infection. [84] Sweet syndrome occurring in children should prompt a workup for possible infection or immunodeficiency, [84] as well as a thorough workup to rule out malignancy.
The predilection for sex appears to depend on the type of Sweet syndrome. Classic or idiopathic Sweet syndrome has a female predominance, with a female-to-male ratio reported to be between 3:1 and 8:1. [5] Drug-induced Sweet syndrome appears also to have a female predilection. [3] However, malignancy-associated Sweet syndrome does not appear to share this predilection. [3, 7] No sex predilection has been observed in children. [84]
Sweet syndrome has no known racial predilection. [2]
Prognosis
Most cases of acute febrile neutrophilic dermatosis resolve, though some persist indefinitely and can be difficult to manage because of pain and skin breakdown. Because Sweet syndrome can be associated with many other diseases, including malignancy, the patient's overall prognosis depends on the underlying cause. [29] As many as 50% of patients may experience recurrence, most often in cases associated with hematologic malignancy or drug reactions.
Patient Education
Patient education should include information about the variable course of this condition, as well as advice on self-monitoring for signs and symptoms of other diseases.
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Red nodules and plaques on lateral aspect of hand.
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Multiple lesions on scalp. Image from Alexa F Boer Kimball, MD, MPH.
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Close-up of scalp lesion. Image from Alexa F Boer Kimball, MD, MPH.
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