Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)

Key Points at a Glance

Highlights of This Disease

• Sweet syndrome (SS) is an autoinflammatory disease characterized by the triad of fever, neutrophilia, and painful erythematous skin lesions.
• It is classified into three subtypes: classical (idiopathic), malignancy-associated, and drug-induced.
• Extracutaneous manifestations include neutrophil infiltration in multiple organs throughout the body, including the eyes, and ocular symptoms occur in up to about one-third of patients.
• Ocular findings most commonly include conjunctivitis, but can present a broad spectrum ranging from scleritis, uveitis, retinal vasculitis, to optic nerve lesions.
• Systemic corticosteroids are the first-line treatment and respond rapidly, including ocular symptoms, but recurrence rates after tapering or discontinuation are high.
• Malignancy-associated type accounts for 25–44% of cases, and screening for hematologic malignancies is particularly important.
• An association with HLA-B54 has been reported in Japanese individuals.

1. What is Sweet syndrome?

Sweet syndrome (SS), first reported by Robert Douglas Sweet in 1964 with eight cases, is also known as acute febrile neutrophilic dermatosis. It is characterized by fever, peripheral neutrophilia, and painful erythematous skin lesions, with pathological findings showing dense infiltration of mature neutrophils in the dermis ⁶⁾. In recent years, it has been classified as an autoinflammatory disease, and involvement of inflammasome gene mutations has been suggested ³⁾.

Epidemiology

• Sex ratio: More common in women, with a female-to-male ratio of approximately 2-3:1
• Age of onset: Adult cases are seen mainly in women aged 30–60 years, but onset can occur in all age groups including children. The mean age of pediatric cases is 5 years, with a male predominance reported in children under 3 years⁴⁾
• Frequency by subtype: Classic (idiopathic) 38-53%, malignancy-associated 25-44%, drug-induced 4-24%
• Recurrence rate: Recurrence occurs in up to one-third of classic SS cases

Three subtypes

Classic (idiopathic)

Often preceded by upper respiratory or gastrointestinal infections.

Associations with inflammatory bowel disease and pregnancy have also been reported.

Accounts for 38–53% of all cases.

Malignancy-associated

Hematologic malignancies account for about 85%, with acute myeloid leukemia (AML) being the most common⁷⁾.

Solid cancers are often gastrointestinal cancers²⁾.

In a retrospective study, 27 of 52 cases (51.9%) were MASS²⁾.

Drug-induced

G-CSF is the most common causative drug.

Associations with ST combination drugs and anticancer drugs (all-trans retinoic acid, proteasome inhibitors, hypomethylating agents) have also been reported.

Induction by vaccines (including SARS-CoV-2) has also been confirmed⁶⁾.

Q Is Sweet syndrome only a skin disease?

A

Skin lesions are the main feature, but up to 50% of cases have extracutaneous symptoms. Neutrophil infiltration can occur in the eyes, musculoskeletal system, as well as multiple organs such as the liver, brain, kidneys, lungs, and spleen.

2. Main symptoms and clinical findings

Subjective symptoms

Systemic symptoms

• Fever: Often seen, but not present in some patients and not essential for diagnosis.
• Headache, muscle pain, joint pain, fatigue: The most common systemic symptoms accompanying skin lesions
• Skin lesions: Violet to erythematous papules, plaques, and nodules appear suddenly and are tender to touch. They occur preferentially on the upper limbs and are asymmetrically distributed

Ocular symptoms

• Redness, irritation, tearing: The most common complaints in anterior segment involvement
• Sudden vision loss: Occurs when accompanied by retinal vasculitis
• Blurred vision, floaters, scotomas: Symptoms suggestive of posterior segment involvement
• Ocular symptoms appear simultaneously with or within a few days of skin findings, and about half of cases are bilateral.

Clinical Findings (Findings Confirmed by Physician Examination)

Ocular lesions associated with SS are highly diverse and can involve almost all parts of the eye and surrounding tissues.

Site	Finding
Orbit/Eyelid	Periorbital erythematous vesicular rash, dacryoadenitis
Anterior segment	Conjunctivitis (most common), episcleritis, scleritis, peripheral ulcerative keratitis, limbal nodules, iritis
Posterior segment	Choroiditis, retinal vasculitis, vitritis
Neuro-ophthalmology	Panuveitis with optic nerve involvement, inflammatory glaucoma

• Periorbital lesions: Painful eyelid swelling with limited eye movement, sometimes misdiagnosed as orbital cellulitis at initial presentation. Responds well to systemic steroids.
• Anterior segment lesions: Conjunctivitis is most common. Iritis, scleritis, and peripheral ulcerative keratitis have also been reported. Even lesions limited to the anterior segment can cause vision loss.
• Posterior segment lesions: Retinal vasculitis typically presents with rapid vision loss. Fundus examination may reveal exudates along vessels and intraretinal hemorrhages.
• Optic nerve lesions: Rarely affects the optic nerve, presenting with vision loss and optic disc edema. Panuveitis and disc edema resolve quickly with steroids or immunomodulatory agents.

Q What is the most common ocular symptom of Sweet syndrome?

A

Conjunctivitis is the most common ocular symptom. In a review of 138 patients with SS, ocular involvement was 3%, but another literature review reported ocular infiltration in about one-third of patients.

3. Causes and Risk Factors

The onset of SS involves background factors corresponding to the three disease types.

Classic (idiopathic) SS

• Upper respiratory tract infections and gastrointestinal infections: Often precede symptom onset by 1 to 3 weeks¹⁾
• Inflammatory bowel disease (IBD) and pregnancy association
• SARS-CoV-2 vaccination: Onset after vaccination with Pfizer-BioNTech, AstraZeneca, Moderna, Janssen, and Sinovac vaccines has been reported, with at least 14 cases confirmed as of 2022⁶⁾

Malignancy-associated Sweet syndrome (MASS)

• Hematologic malignancies (especially AML) account for approximately 85%⁷⁾
• In a cohort of 2,178 adult AML patients, 21 cases (1%) had SS, one of which presented with SS prior to AML diagnosis⁵⁾
• Among solid tumors, gastrointestinal cancers such as esophageal, colorectal, and gastric cancers are common ²⁾
• FLT3 mutations and myelodysplasia-related AML have been reported as risk factors for MASS ⁵⁾

Drug-induced Sweet syndrome

• G-CSF is the most common causative drug
• Hydroxychloroquine: at least 4 cases have been reported³⁾
• Estimated to be less than 10% of all cases³⁾
• In an analysis of the French pharmacovigilance database, 136 out of 994,789 cases were related to SS³⁾

Genetic Predisposition

• HLA-B54 / HLA-Cw1: High frequency reported in Neuro-Sweet disease, particularly in Japanese patients⁹⁾
• MEFV gene mutation: Identified in Sweet syndrome associated with myelodysplastic syndrome⁶⁾

Prevention and daily care

There is no established method to prevent Sweet syndrome itself. If fever or painful skin lesions (red raised bumps) suddenly appear, promptly consult a dermatologist. Especially if you are undergoing treatment for a blood disease or using anticancer drugs, inform your primary physician if skin symptoms occur.

4. Diagnosis and testing methods

Diagnostic criteria

The diagnostic criteria for SS were proposed by Su & Liu in 1986 and revised by Von den Driesch in 1994.

Classic SS / malignancy-associated SS: Meets all 2 major criteria plus 2 of the 4 minor criteria.

• Major criteria:
  • ① Sudden onset of painful erythematous plaques or nodules
  • ② Histopathological evidence of dense neutrophilic infiltration without evidence of leukocytoclastic vasculitis
• Minor criteria:
  • ③ Fever (>38°C)
  • ④ Association with underlying diseases (hematologic malignancies, visceral malignant tumors, inflammatory diseases, pregnancy), or preceding upper respiratory/gastrointestinal infection or vaccination
  • ⑤ Excellent therapeutic response to systemic steroids or potassium iodide
  • ⑥ Abnormal laboratory values at onset (3 out of 4: ESR >20 mm/hr, CRP positive, WBC >8,000, neutrophils >70%)

Drug-induced SS: All 5 criteria A–E must be met.

• A. Sudden appearance of painful erythematous plaques/nodules
• B. Histopathology showing dense neutrophilic infiltration without vasculitis
• C. Fever (>38°C)
• D. Temporal relationship between drug intake and symptom onset
• E. Resolution of lesions after drug discontinuation or steroid therapy

Blood Tests

• Complete Blood Count (CBC): Peripheral blood neutrophilia (leukocytosis with increased neutrophils) is the most consistent abnormality
• Acute Phase Reactants: Elevated ESR and CRP
• Biochemistry and urinalysis: Abnormalities suggest extracutaneous involvement
• Workup for malignancy: If anemia, neutropenia, or platelet abnormalities are present, consider bone marrow biopsy²⁾

Skin biopsy

• Useful for definitive diagnosis. Characteristic findings include dense infiltration of mature neutrophils in the dermis with nuclear dust, without vasculitis¹⁾
• However, some long-standing cases may show vasculitis, and some experts argue that the presence of vasculitis alone should not exclude the diagnosis⁶⁾

Ophthalmic evaluation

• Slit-lamp microscopy and fundus examination: Should be performed in all cases to evaluate the anterior and posterior segments.
• Fluorescein fundus angiography (FA): Reveals ischemic changes and corkscrew vessels consistent with retinal vasculitis.
• Enhanced depth imaging OCT (EDI-OCT) and B-mode ultrasonography: Useful for identifying choroidal infiltration and diffuse scleritis.
• Brain MRI: Performed when optic nerve involvement is suspected. May show enhancement of the optic nerve.

Differential Diagnosis

• Erythema multiforme (EM): History of herpes simplex infection; inflammatory markers normal to moderate.
• Erythema nodosum (EN): Skin lesions are limited to the lower extremities, and biopsy histology differs.
• Behçet’s disease: Typical uveitis or vasculitis on skin biopsy serve as differentiating points. In neurological lesions, associations with HLA-B51 in Behçet’s disease and HLA-B54/HLA-Cw1 in Neuro-Sweet disease are reported, with the former having a worse prognosis than the latter^1,9)
• Orbital cellulitis: Periorbital SS is often misdiagnosed.

Uveitis can also occur in other systemic inflammatory diseases such as polyarteritis nodosa, granulomatosis with polyangiitis (Wegener’s granulomatosis), and SLE, so differentiation based on diagnostic criteria is essential.

5. Standard Treatment

Systemic Corticosteroid Therapy (First-line)

Systemic corticosteroids are the first-line treatment for SS regardless of disease subtype.

• Prednisone 0.5–1 mg/kg/day is widely used, with prompt response obtained in most cases⁸⁾
• Prednisone 0.5–1 mg/kg/day is widely used, with prompt response obtained in most cases⁸⁾

Management by Disease Subtype

• Malignancy-associated SS: Skin lesions may resolve with treatment of the underlying malignancy²⁾. Even if unresponsive to steroids, improvement can occur with initiation of antileukemic therapy.
• Drug-induced SS: Discontinuation of the causative drug is fundamental, with systemic steroids added depending on severity⁸⁾

Treatment of Ocular Symptoms

• Anterior segment and periorbital lesions respond well to systemic steroids, and additional topical steroids are rarely required.
• For anterior uveitis (iritis), steroid eye drops (betamethasone or dexamethasone) combined with mydriatic eye drops are used to prevent posterior synechiae.
• In severe posterior segment lesions, intraocular steroids may improve outcomes.
• For vision-threatening retinal vasculitis, intravitreal bevacizumab injection or retinal photocoagulation may be necessary.

Steroid-Sparing Agents (Alternative/Adjuvant Therapy)

• Colchicine, dapsone, potassium iodide, indomethacin
• Immunosuppressants: cyclophosphamide, cyclosporine, tacrolimus, azathioprine¹⁾
• Acitretin: In a single-center retrospective study of reactive neutrophilic dermatosis associated with adult-onset immunodeficiency due to anti-IFN-γ autoantibodies, all 23 cases with 27 episodes (SS 20, generalized pustular eruption 7) responded, and 70.4% showed near-complete or complete resolution within 2 weeks. As an uncontrolled study in a special background population, caution is required when extrapolating to general SS¹⁰⁾

Precautions and side effects in treatment

Note that the recurrence rate is high after tapering or discontinuing systemic steroids. Also, long-term steroid use in the treatment of uveitis carries a risk of steroid-induced glaucoma, so once inflammation subsides, consider switching to eye drops with fewer side effects, such as fluorometholone. In idiopathic SS, occult hematologic malignancies may become apparent up to 16 months after the onset of skin and ocular symptoms, so regular monitoring is necessary.

Q Can Sweet syndrome recur after treatment?

A

The recurrence rate after tapering or discontinuing steroids is high regardless of disease type. However, for ocular symptoms, refractory or recurrent conditions are extremely rare, and permanent visual impairment is unlikely except in severe retinal vasculitis.

6. Pathophysiology and Detailed Pathogenesis

The exact pathophysiology of SS has not yet been fully elucidated, but a hypersensitivity reaction mediated by IL-1-activated cytokines and neutrophils is considered the main mechanism.

Cytokines and Inflammatory Mediators

In SS skin lesions, the following inflammatory cell markers are elevated compared to non-SS patients and other neutrophilic dermatoses:

• CD3 (T cell marker)
• CD163 (macrophage marker)
• Myeloperoxidase (MPO)
• Metalloproteinases
• Vascular endothelial growth factor (VEGF)

In addition, elevations of IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-17, TNF-α, and IFN-γ, as well as increased expression of Toll-like receptors and C-type lectin innate immune receptors have been reported⁶⁾.

Autoinflammatory mechanisms

In recent years, SS has been classified as an autoinflammatory disease, and it has been suggested that mutations in inflammasome genes may be involved in the persistence of inflammation³⁾. Circulating autoantibodies, dermal dendritic cells, immune complexes, leukocyte migration mechanisms, and type 1 helper T cells have been suggested as contributing factors to the pathogenesis.

Genetic Predisposition

• HLA-B54 / HLA-Cw1: A high frequency has been reported in Neuro-Sweet disease⁹⁾
• In Neuro-Behçet’s disease, a strong association with HLA-B51 has been reported, serving as a useful finding for differentiation⁹⁾

Mechanism of Malignancy-Associated SS

Regarding the pathogenesis of MASS, there are two hypotheses: a hypersensitivity reaction to tumor antigens and overproduction/dysregulation of inflammatory cytokines²⁾. The fact that skin symptoms improve with treatment of the underlying malignancy even in steroid-refractory MASS patients supports the hypersensitivity reaction hypothesis.

Pathophysiology of Ocular Lesions

As of 2022, there is no literature describing a unique pathophysiology specific to ocular lesions in SS, but it is presumed that similar autoinflammatory mechanisms as in systemic disease are involved.

Q How do you differentiate Sweet syndrome from Behçet's disease?

A

Both are clinically similar, but in Behçet’s disease, typical uveitis or vasculitis on skin biopsy, and in Neuro-Behçet’s disease, association with HLA-B51 serve as useful findings for differentiation. SS typically shows neutrophilic infiltration without vasculitis, while Neuro-Sweet disease frequently exhibits HLA-B54 and HLA-Cw1 and is considered to have a better prognosis than Neuro-Behçet’s disease.

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7. Latest Research and Future Perspectives (Reports at Research Stage)

For patients: Please read this

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Neuro-Sweet disease (NSS)

A neurological complication of SS proposed in 1999, with fewer than 70 cases reported in the literature ¹⁾. It presents as encephalitis or aseptic meningitis, with headache and altered consciousness being common. MRI findings show asymmetric signal abnormalities on T2/FLAIR in the brainstem, cortex, and thalamus.

Acurio & Chuquilin (2023) reported a case of a 51-year-old woman diagnosed with ADEM (acute disseminated encephalomyelitis) 10 years earlier who relapsed and was definitively diagnosed with SS by skin biopsy. Extensive FLAIR hyperintensity on brain MRI almost completely resolved one month after steroid treatment ¹⁾.

The diagnostic criteria proposed by Hisanaga in 2005 evaluate four items: steroid-responsive neurological symptoms, skin findings, absence of uveitis or cutaneous vasculitis characteristic of Behçet’s disease, and identification of HLA-Cw1 or HLA-B54. If the first three items are met, a diagnosis of probable NSS is made. However, these criteria are based on a cohort of Japanese patients, and their applicability to other populations has not been sufficiently validated¹⁾.

SARS-CoV-2 vaccine and SS

Bechtold & Owczarczyk-Saczonek (2022) identified 14 cases of SS following SARS-CoV-2 vaccination in case reports (including their own case) and a literature review. Reports existed for mRNA, viral vector, and inactivated vaccines, encompassing diverse clinical presentations such as joint symptoms, neurological symptoms, cellulitis-like, and bullous forms⁶⁾.

SS as initial presentation of malignancy

Liu et al. (2025) reported a case of an 18-year-old female diagnosed with AML carrying the DEK::NUP214 fusion gene, with SS as the initial symptom. It was emphasized that SS can precede malignancy and the importance of hematological workup when skin symptoms appear ⁵⁾.

Future challenges

• Elucidation of pathophysiology specific to ocular involvement in SS
• Development of treatment guidelines for neutrophilic dermatoses in general (currently insufficient evidence) ⁶⁾
• Development of molecular targeted therapies based on autoinflammatory mechanisms

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8. References

1. Acurio K, Chuquilin M. Neuro-Sweet Syndrome: A Diagnostic Conundrum. Neurohospitalist. 2023;13(4):406-409. doi:10.1177/19418744231174949.
2. Bagos-Estevez AG, Moore S, Turner L, Baldwin B. A Case of Bullous Sweet’s Syndrome Associated With Esophageal Adenocarcinoma. Cureus. 2024;16(1):e52954. doi:10.7759/cureus.52954. PMID:38406046; PMCID:PMC10894071.
3. Almeida-Silva G, Antunes J, Tribolet de Abreu I, Monteiro F, Vasconcelos P, Soares-Almeida L, et al. Hydroxychloroquine-induced Sweet’s Syndrome: A Case Report and Literature Review. Acta dermato-venereologica. 2025;105:adv41333. doi:10.2340/actadv.v105.41333. PMID:39780415; PMCID:PMC11736664.
4. Zhou AE, Weddington CM, Ge S, Hoegler KM, Driscoll MS. Pediatric sweet syndrome. Clin Case Rep. 2021;9(10):e04762. doi:10.1002/ccr3.4762. PMID:34707864; PMCID:PMC8527021.
5. Liu H, Liu GX, Liu FH, Wang SG. Acute myeloid leukemia with DEK::NUP214 fusion resembling acute promyelocytic leukemia, initially presenting as sweet syndrome: A case report and literature review. J Int Med Res. 2025;53(3):3000605251327476. doi:10.1177/03000605251327476. PMID:40138481; PMCID:PMC11951429.
6. Bechtold A, Owczarczyk-Saczonek A. Atypical presentation of Sweet syndrome with nodular erythema and oral ulcerations provoked by Ad26.COV2.S SARS-CoV-2 vaccination and review of literature. Dermatol Ther. 2022;35(12):e15923. doi:10.1111/dth.15923. PMID:36219526; PMCID:PMC9874627.
7. Maronese CA, Derlino F, Moltrasio C, Cattaneo D, Iurlo A, Marzano AV. Neutrophilic and eosinophilic dermatoses associated with hematological malignancy. Front Med (Lausanne). 2023;10:1324258. doi:10.3389/fmed.2023.1324258. PMID:38249974; PMCID:PMC10796805.
8. Joshi TP, Friske SK, Hsiou DA, Duvic M. New Practical Aspects of Sweet Syndrome. Am J Clin Dermatol. 2022;23(3):301-318. doi:10.1007/s40257-022-00673-4. PMID:35157247; PMCID:PMC8853033.
9. Hisanaga K. Neuro-Behçet Disease, Neuro-Sweet Disease, and Spectrum Disorders. Intern Med. 2022;61(4):447-450. doi:10.2169/internalmedicine.8227-21. PMID:34615825; PMCID:PMC8907766.
10. Rujiwetpongstorn R, Chuamanochan M, Tovanabutra N, Chaiwarith R, Chiewchanvit S. Efficacy of acitretin in the treatment of reactive neutrophilic dermatoses in adult-onset immunodeficiency due to interferon-gamma autoantibody. J Dermatol. 2020;47(6):563-568. doi:10.1111/1346-8138.15312. PMID:32207168; PMCID:PMC7318687.