What are the differential diagnoses to consider for a patient presenting with symptoms suggestive of Systemic Lupus Erythematosus (SLE)?

Differential Diagnoses for Systemic Lupus Erythematosus

When evaluating a patient with suspected SLE, consider these 10 key differential diagnoses that can mimic its multisystem presentation, with particular attention to conditions that require distinct management strategies to prevent morbidity and mortality.

Autoimmune and Rheumatologic Conditions

1. Antiphospholipid Antibody Syndrome (Primary)

• Can present independently with thrombotic cerebrovascular disease, multisystem involvement, and cytopenias that overlap significantly with SLE manifestations 1
• Critical distinction: Requires anticoagulation rather than immunosuppression alone, making this differentiation potentially life-saving 1
• Test for persistent moderate-to-high anticardiolipin, anti-β2-glycoprotein IgG/IgM, or lupus anticoagulant 2

2. Drug-Induced Lupus

• Common culprits include hydralazine, procainamide, isoniazid, and anti-TNF agents 3
• Typically resolves with discontinuation of the offending medication 3
• Anti-histone antibodies are often positive, while anti-dsDNA and anti-Smith antibodies are typically negative 4

3. Mixed Connective Tissue Disease

• Overlapping features of SLE, systemic sclerosis, and polymyositis 5
• Distinguished by high-titer anti-U1-RNP antibodies 5
• May have prominent Raynaud's phenomenon and puffy hands 5

4. Sjögren's Syndrome

• Can present with arthritis, cytopenias, and positive ANA 6
• Sicca symptoms (dry eyes and mouth) are prominent 6
• Anti-Ro/SSA and anti-La/SSB antibodies help differentiate 6

Immune Dysregulation Syndromes

5. Autoimmune Lymphoproliferative Syndrome (ALPS)

• Presents with lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias mimicking SLE 1
• Key feature: Prominent lymphoproliferation that may be more striking than typical SLE 1
• Consider particularly when these features dominate the clinical picture 1

Infectious Mimickers

6. Chronic Infections (HIV, Hepatitis C, Lyme Disease, HTLV-1)

• Critical pitfall: The most dangerous error is attributing symptoms to lupus without adequately ruling out infection, especially in immunosuppressed patients 7
• HIV can cause positive ANA, cytopenias, and multisystem involvement 1
• Lyme disease mimics SLE with neurological and arthritic manifestations 1
• HTLV-1 testing recommended in endemic areas or at-risk populations 1
• Hepatitis C can cause cryoglobulinemia with similar renal and cutaneous findings 6

7. Subacute Bacterial Endocarditis

• Can present with fever, arthritis, glomerulonephritis, and positive ANA 2
• Distinguishing feature: Significantly elevated CRP (>50 mg/L) should prompt exclusion of infection in suspected SLE, as SLE patients rarely have markedly elevated CRP 2
• Blood cultures and echocardiography are essential 2

Neurological Conditions

8. Multiple Sclerosis

• Presents with multifocal neurological deficits, particularly in young women, overlapping with neuropsychiatric SLE 1
• Distinguishing features: MRI showing periventricular white matter lesions with specific distribution patterns and CSF oligoclonal bands 1
• The average sensitivity of MRI in active NPSLE is only 57%, and small punctate hyperintense T2-weighted lesions are non-specific (specificity 60-82%) 2

Hematologic Malignancies

9. Lymphoproliferative Disorders (Non-Hodgkin's Lymphoma)

• SLE patients have increased risk for non-Hodgkin's lymphoma 2
• Can present with cytopenias, lymphadenopathy, and constitutional symptoms 2
• Lymph node biopsy may be necessary when lymphadenopathy is prominent or atypical 1

Dermatologic Mimics

10. Other Cutaneous Conditions (Rosacea, Dermatomyositis, Cutaneous Vasculitis)

• Many conditions mimic lupus-specific cutaneous lesions and require evaluation by an experienced dermatologist with skin biopsy for histological analysis 2
• Dermatomyositis has characteristic heliotrope rash and Gottron's papules with muscle involvement 6
• Repeat biopsy is recommended if lesion morphology changes or treatment fails 2

Critical Diagnostic Approach

The diagnostic workup must systematically exclude these differentials before attributing symptoms to SLE:

• Mandatory initial testing: ANA at 1:160 dilution cutoff (entry criterion for SLE classification) 1
• If ANA positive: Anti-dsDNA, anti-Smith, complement levels (C3, C4), CBC, comprehensive metabolic panel, urinalysis with microscopy 1
• Antiphospholipid antibody testing: Essential in all suspected cases to determine if anticoagulation is needed 1
• Infection exclusion: CSF analysis with cell count, protein, glucose, Gram stain, culture, and viral PCR (HSV, JC virus) when fever, altered mental status, or meningeal signs present 8, 7
• Neuroimaging: Brain MRI with gadolinium-enhanced T1 sequences and diffusion-weighted imaging to exclude stroke, hemorrhage, or infection 8, 7

Common Pitfalls to Avoid

• Never attribute neurological symptoms to lupus without imaging and appropriate exclusion of infection, stroke, or hemorrhage 8, 7
• Significantly elevated CRP (>50 mg/L) in suspected SLE should trigger aggressive infection workup rather than assuming lupus activity 2
• Normal CBC, renal function, and liver enzymes do not exclude active CNS lupus, as neurological involvement can occur independently 8