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

Differential Diagnoses for Young Girls Presenting with SLE-Like Features

When evaluating a young girl with suspected SLE, the most critical differentials to exclude are antiphospholipid antibody syndrome, acute disseminated encephalomyelitis, primary immunodeficiency syndromes (particularly immune dysregulation disorders), mixed connective tissue disease, and infectious mimickers including HTLV1, Lyme disease, and meningovascular syphilis. 1, 2, 3

Autoimmune and Rheumatologic Differentials

Antiphospholipid Antibody Syndrome

• Can present with multisystem involvement including thrombotic cerebrovascular disease, which is common in SLE patients but may occur independently 1
• Requires testing for antiphospholipid antibodies in all suspected cases, as this determines anticoagulation strategy rather than immunosuppression alone 1, 2
• May coexist with SLE, making distinction challenging, but isolated antiphospholipid syndrome lacks other SLE serological markers 2

Mixed Connective Tissue Disease

• Presents with overlapping features of SLE, particularly myositis, which can be a rare first presentation mimicking SLE 4
• Distinguished by anti-U1-RNP antibodies (though these can also occur in SLE) and typically lacks anti-dsDNA and anti-Smith antibodies 4
• Muscle weakness with elevated creatinine kinase should prompt consideration of this diagnosis 4

Juvenile Dermatomyositis

• Presents with proximal muscle weakness, characteristic rashes (heliotrope rash, Gottron's papules), and elevated muscle enzymes 4
• Can be distinguished from SLE-associated myositis by specific antibody profiles and muscle biopsy findings 4

Immune Dysregulation Syndromes

Autoimmune Lymphoproliferative Syndrome (ALPS)

• Presents with lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias that can mimic SLE 1
• Distinguished by elevated double-negative T cells (CD4-CD8-) and defects in Fas-mediated apoptosis 1
• Consider when lymphoproliferation and autoimmunity are prominent features 1

IPEX Syndrome and Related Disorders

• Presents with polyendocrine autoimmunity, which can overlap with SLE manifestations 1
• Consider when multiple food/environmental allergies accompany autoimmune features 1
• Typically presents earlier in childhood than typical SLE 1

Hemophagocytic Lymphohistiocytosis (HLH)

• Can present acutely with high fever, hepatosplenomegaly, and cytopenias mimicking severe SLE flare 1
• Requires urgent recognition as it represents a medical emergency 1
• Distinguished by ferritin >10,000 ng/mL, hypertriglyceridemia, and hemophagocytosis on bone marrow biopsy 1

Neurological Differentials

Multiple Sclerosis

• Can present with multifocal neurological deficits, particularly in young women, overlapping with neuropsychiatric SLE 1
• Distinguished by MRI showing periventricular white matter lesions with specific distribution patterns and CSF oligoclonal bands 1
• Requires careful application of McDonald criteria, particularly in atypical presentations 1

Acute Disseminated Encephalomyelitis (ADEM)

• Monophasic demyelinating disease that can mimic neuropsychiatric SLE 1
• Should not be diagnosed as SLE unless new symptoms appear >3 months after clinical onset 1
• Distinguished by preceding viral illness and characteristic MRI findings 1

Neuromyelitis Optica (Devic's Syndrome)

• Presents with optic neuritis and transverse myelitis, which can occur in SLE 1
• Distinguished by aquaporin-4 antibodies and longitudinally extensive spinal cord lesions 1
• Some consider this a variant of SLE, others a separate entity 1

Infectious Mimickers

HTLV1 Infection

• Can present with striking similarities to SLE, including neurological manifestations 1
• Requires serological testing in endemic areas or at-risk populations 1

Lyme Disease

• Can mimic SLE with multisystem involvement, particularly neurological and arthritic manifestations 1
• Requires serological testing and consideration of geographic exposure 1

Meningovascular Syphilis

• Can present with multifocal cerebral lesions mimicking neuropsychiatric SLE 1
• Requires syphilis serologies (RPR/VDRL and treponemal testing) in all cases with neurological involvement 1

Herpes Simplex Encephalitis

• Must be excluded in patients presenting with acute neuropsychiatric symptoms, particularly with fever 1, 3
• Requires lumbar puncture for CSF analysis and PCR testing 1
• Critical to exclude before attributing symptoms to SLE, especially in immunosuppressed patients 3

Vascular and Thrombotic Disorders

Cerebral Ischemia/Infarction from Non-SLE Causes

• Phospholipid antibody syndrome (can occur without SLE) 1
• CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) 1
• Takayasu's arteritis 1
• Carotid dissection 1
• Distinguished by vascular imaging (MR angiography, CT angiography) and specific genetic/serological testing 1

Metabolic and Drug-Induced Conditions

Drug-Induced Lupus

• Can be caused by medications including hydralazine, procainamide, isoniazid, and anti-TNF agents 3
• Distinguished by anti-histone antibodies, absence of anti-dsDNA and anti-Smith antibodies, and resolution after drug discontinuation 3

Steroid-Induced Psychosis

• Must be considered in patients already on corticosteroids presenting with neuropsychiatric symptoms 1, 3
• Although rare, it can mimic SLE-associated psychosis 1
• Temporal relationship to steroid initiation or dose escalation is key 3

Metabolic Abnormalities

• Hypertension, electrolyte disturbances, and uremia can cause neuropsychiatric symptoms mimicking SLE 1, 3
• Requires comprehensive metabolic panel and blood pressure monitoring 1

Malignancy-Related Conditions

Paraneoplastic Cerebellar Ataxia

• Can present with neurological symptoms mimicking SLE, particularly in young adults 1
• Distinguished by elevated CSF IgG and specific paraneoplastic antibodies 1
• Requires malignancy screening when suspected 1

Lymphoma

• Non-Hodgkin lymphoma risk is increased in SLE patients, but can also present with SLE-like features 2
• Consider when lymphadenopathy is prominent and progressive 1

Critical Diagnostic Approach

Essential Initial Testing

• ANA testing (mandatory entry criterion for SLE classification) with 1:160 dilution cutoff 2, 5
• If ANA positive: anti-dsDNA (double-screening strategy), anti-Smith, complement levels (C3, C4), complete blood count, comprehensive metabolic panel, urinalysis with microscopy 2, 5
• Antiphospholipid antibody panel (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) 2, 5

Neuropsychiatric Presentation Workup

• MRI brain to exclude structural lesions, ischemia, or demyelination 1
• EEG for seizure evaluation 1
• Lumbar puncture for CSF analysis to exclude infection, particularly in immunosuppressed patients 1, 3
• Consider infectious serologies (HTLV1, Lyme, syphilis) based on clinical context 1

Key Pitfalls to Avoid

• Never attribute neuropsychiatric symptoms to SLE without excluding infection (especially in immunosuppressed patients), metabolic causes, or medication side effects 1, 3
• Do not diagnose SLE in monophasic demyelinating diseases unless new symptoms appear >3 months after onset 1
• Do not overlook the possibility of coexisting conditions, particularly antiphospholipid syndrome requiring different management 1, 2
• Recognize that ANA negativity essentially excludes SLE according to current classification criteria 2, 5