What is the diagnosis and treatment approach for a patient with Sweet syndrome, considering potential underlying conditions such as infections, inflammatory diseases, or malignancies?

Sweet Syndrome: Diagnosis and Management

Overview and Clinical Presentation

Sweet syndrome (acute febrile neutrophilic dermatosis) is diagnosed by the characteristic triad of tender erythematous papules/nodules/plaques, fever, and neutrophilia, with skin biopsy showing dense dermal neutrophilic infiltrate being essential for definitive diagnosis. 1

The syndrome presents with:

• Tender, erythematous, edematous papules, nodules, or plaques that commonly appear on the upper limbs, trunk, and head/neck regions 1, 2
• Fever and elevated neutrophil count as hallmark systemic features 3, 4
• Skin lesions developing over 24-48 hours with potential for recurrence 5
• Painful cutaneous manifestations that may be accompanied by extracutaneous involvement 3, 6

Diagnostic Approach

Essential Diagnostic Steps

Skin biopsy from an active lesion is mandatory for definitive diagnosis and should be performed on the periphery of the lesion to demonstrate the characteristic dense dermal neutrophilic infiltrate without leucocytoclastic vasculitis 1, 3. Failure to perform skin biopsy leads to misdiagnosis 1.

Thorough clinical examination must identify:

• Distribution and morphology of skin lesions (distinguishing from bowel-associated dermatosis-arthritis syndrome by upper limb distribution and lack of ulceration) 5
• Presence of fever patterns and systemic symptoms 4
• Evidence of potential underlying conditions 7

Laboratory Evaluation

Complete blood count revealing neutrophilia is a key diagnostic feature 3, 6. In patients with Sweet syndrome, hemoglobin levels should be carefully evaluated, as significantly lower hemoglobin (in both males and females) strongly suggests malignancy-associated Sweet syndrome rather than classic or drug-induced variants 4.

Critical Differential Diagnosis

The following conditions must be systematically excluded before confirming Sweet syndrome 1:

• Infections (bacterial, fungal, viral, or parasitic) requiring cultures and serological testing 1
• Drug eruptions and chemotherapy/radiation-induced reactions 1
• Cutaneous infiltration from underlying malignancy 1
• Erythema multiforme and leukocytoclastic vasculitis 1
• Bowel-associated dermatosis-arthritis syndrome (distinguished by vesiculopustular morphology, more rapid resolution within 8 days, and upper limb distribution) 5
• Pyoderma gangrenosum (distinguished by ulceration and necrosis) 5

Classification and Associated Conditions

Sweet syndrome is classified into three clinical subtypes 3, 7:

1. Classical (Idiopathic) Sweet Syndrome (53% of cases)

• Often preceded by upper respiratory tract infection 7, 6
• May be associated with inflammatory bowel disease and pregnancy 7
• Represents the majority of cases without underlying malignancy 4

2. Malignancy-Associated Sweet Syndrome (35% of cases)

Approximately 21-35% of Sweet syndrome patients have an associated malignancy, most commonly hematologic disorders 4, 7. This variant requires aggressive evaluation because:

• 21 patients in one series had hematologic malignancy or myeloproliferative/myelodysplastic disorders, while 6 had solid tumors 4
• Sweet syndrome may be the first sign of malignancy or herald its recurrence 7
• Anemia is a key distinguishing feature suggesting underlying malignancy 4

Specific malignancy screening should include:

• Complete hematologic evaluation for leukemia, lymphoma, and myelodysplastic syndromes 4, 7
• Age-appropriate cancer screening for solid tumors 4
• Bone marrow biopsy when hematologic abnormalities are present 7

3. Drug-Induced Sweet Syndrome (12% of cases)

Several anticancer agents are potential triggers, including all-trans-retinoic acid, proteasome inhibitors, hypomethylating agents, tyrosine kinase inhibitors, and lenalidomide 7. Growth factors used in cancer patients have increased the incidence of this variant 7.

Associated Conditions Requiring Evaluation

50-70% of Sweet syndrome cases are associated with underlying systemic disorders 8, necessitating evaluation for:

• Inflammatory bowel disease (particularly ulcerative colitis and Crohn's disease), which forms part of the spectrum of neutrophilic dermatoses in IBD 5
• Infections, particularly upper respiratory tract infections, with Mycoplasma pneumoniae specifically associated with mucous membrane-predominant variants 1
• Rheumatologic disorders including spondyloarthropathies 8
• Hematologic malignancies as the most common associated cancer type 4, 7

Treatment Algorithm

First-Line Therapy

Systemic corticosteroids remain the gold standard treatment and were used in 70% of patients with typically complete response 3, 4. The treatment approach should be:

For patients without contraindications to corticosteroids:

• Initiate systemic corticosteroids as first-line therapy 3, 2
• Topical and/or intralesional corticosteroids may be effective as monotherapy for limited disease or as adjuvant therapy 3
• Expect rapid resolution of symptoms and lesions 3, 6

Alternative First-Line Options

For patients with potential systemic infection or corticosteroid contraindications, initiate treatment with 3:

• Potassium iodide (typically results in rapid resolution) 3, 2
• Colchicine (typically results in rapid resolution) 3, 2

These agents are reasonable first-line alternatives because they avoid immunosuppression in potentially infected patients 3.

Second-Line and Refractory Disease

For corticosteroid-refractory cases or as steroid-sparing agents, consider 3, 2:

• Dapsone (requires appropriate laboratory monitoring for severe adverse effects) 3, 2
• Cyclosporine (requires appropriate laboratory monitoring for severe adverse effects) 3, 2
• Indomethacin (appears less effective than corticosteroids, potassium iodide, and colchicine) 3
• Clofazimine (appears less effective than first-line agents) 3

Traditional immunosuppressants, biologic agents, and small molecules have been described as effective in treating refractory Sweet syndrome 2.

Special Circumstances

For drug-induced Sweet syndrome:

• Spontaneous resolution may occur after withdrawal of the causative medication 3, 7
• Some cases require temporary discontinuation of anticancer agents, systemic corticosteroids, and/or rechallenge with either the same or different agents 7

For impetiginized or secondarily infected lesions:

• Systemic antibacterials with activity against Staphylococcus aureus frequently result in partial improvement 3
• Organism-sensitive specific systemic antibacterials have been helpful when dermatosis-associated bacterial infections are present 3

For malignancy-associated Sweet syndrome:

• Treatment must target both the Sweet syndrome and the underlying malignancy 8, 7
• Cytotoxic chemotherapy and antimetabolic drugs are used for the underlying disorder but seldom solely for Sweet syndrome management 3

Critical Pitfalls to Avoid

Failure to perform skin biopsy is the most common diagnostic error and leads to misdiagnosis 1. Always biopsy an active lesion from the periphery 1.

Overlooking underlying malignancy is a serious error, particularly when anemia is present—always evaluate hemoglobin levels and pursue malignancy screening when levels are significantly reduced 4.

Misdiagnosing as infection can occur when fever and neutrophilia dominate the presentation—systematic exclusion of infectious causes through cultures and serological testing is mandatory before initiating immunosuppressive therapy 1.

Confusing with bowel-associated dermatosis-arthritis syndrome can delay appropriate IBD evaluation—distinguish by lesion morphology (vesiculopustular vs. papules/plaques) and time course (8 days vs. longer duration) 5.

Prognosis and Follow-Up

More than 25% of patients experience recurrence following successful treatment, often in the same location as the initial episode 8. This high recurrence rate necessitates long-term monitoring and patient education about early recognition of recurrent lesions.

Some cases resolve spontaneously without disease-specific therapeutic intervention, particularly in patients for whom treatment was not initiated 3. However, given the association with serious underlying conditions, observation without treatment should only be considered in carefully selected cases without systemic symptoms or concerning features.