What are the differential diagnoses for a woman of childbearing age presenting with joint pain, fever, fatigue, and skin rashes, suspected of having Systemic Lupus Erythematosus (SLE)?

Differential Diagnoses for Systemic Lupus Erythematosus

When evaluating a woman of childbearing age with joint pain, fever, fatigue, and skin rashes, the differential diagnosis must systematically exclude rheumatoid arthritis, viral infections (particularly Epstein-Barr virus), drug-induced lupus, mixed connective tissue disease, dermatomyositis, adult-onset Still's disease, and antiphospholipid syndrome before confirming SLE. 1, 2

Primary Rheumatologic Differentials

Rheumatoid Arthritis

• Symmetrical polyarthritis involving metacarpophalangeal joints, proximal interphalangeal joints, wrists, elbows, shoulders, and knees distinguishes RA from SLE 3
• Presence of rheumatoid factor and anti-citrullinated protein antibodies (anti-CCP) supports RA diagnosis, though these can occasionally appear in SLE patients 3
• Joint erosions on plain radiographs favor RA over SLE, as SLE typically causes non-erosive arthritis 3
• RA patients lack the malar rash, photosensitivity, and renal involvement characteristic of SLE 2

Mixed Connective Tissue Disease (MCTD)

• Presents with overlapping features of SLE, systemic sclerosis, and polymyositis 1
• Distinguished by high-titer anti-U1-RNP antibodies in the absence of anti-Sm or anti-dsDNA antibodies 3, 1
• Raynaud's phenomenon and puffy hands are more prominent than in SLE 1

Dermatomyositis/Polymyositis

• Proximal muscle weakness (difficulty standing, lifting arms) is the hallmark, not just myalgia 3
• Elevated creatine kinase (CK) levels differentiate myositis from SLE-associated myalgia 3
• Heliotrope rash and Gottron's papules are specific to dermatomyositis, distinct from malar rash 3
• EMG shows muscle fibrillations and MRI demonstrates muscle inflammation 3

Infectious Differentials

Viral Infections (Epstein-Barr Virus, Parvovirus B19, HIV)

• EBV infection can trigger SLE onset and presents with similar constitutional symptoms, arthralgia, and rash 1
• Acute viral syndromes typically resolve within weeks, whereas SLE persists with chronic relapsing course 2, 4
• HIV testing is mandatory before initiating immunosuppression for presumed SLE 5
• Parvovirus B19 causes arthritis and rash but lacks the autoantibody profile of SLE 1

Septic Arthritis and Systemic Infections

• Monoarticular joint involvement with purulent synovial fluid indicates septic arthritis, not SLE polyarthritis 3
• SLE patients have increased infection risk due to disease and immunosuppression, making infection exclusion critical before attributing symptoms to lupus flare 3, 6
• Urinary tract infections and respiratory infections are particularly common in SLE patients 3

Drug-Induced Lupus

• Caused by hydralazine, procainamide, isoniazid, minocycline, and anti-TNF agents 1
• Presents with arthralgia, serositis, and positive ANA, but typically lacks renal and CNS involvement 1
• Anti-histone antibodies are present in drug-induced lupus but not specific 1
• Symptoms resolve within weeks to months after discontinuing the offending drug 1

Other Autoimmune Conditions

Adult-Onset Still's Disease

• Quotidian fever pattern (daily temperature spikes to ≥39°C) with evanescent salmon-pink rash 3
• Markedly elevated ferritin (often >1000 ng/mL) and inflammatory markers distinguish Still's disease 3
• Lacks the specific autoantibodies (anti-dsDNA, anti-Sm) seen in SLE 2

Antiphospholipid Syndrome (APS)

• Can occur independently or overlap with SLE in up to 40% of patients 3, 7
• Thrombotic events (arterial or venous), recurrent pregnancy loss, and thrombocytopenia are hallmarks 3, 7
• Requires positive anticardiolipin, anti-β2-glycoprotein I, or lupus anticoagulant on two occasions 12 weeks apart 7

Sjögren's Syndrome

• Sicca symptoms (dry eyes, dry mouth) predominate over systemic manifestations 3
• Anti-SSA (Ro) and anti-SSB (La) antibodies can appear in both Sjögren's and SLE 3
• Parotid gland enlargement and positive Schirmer's test support Sjögren's diagnosis 3

Hematologic and Vascular Differentials

Immune Thrombocytopenic Purpura (ITP)

• Isolated thrombocytopenia without other cytopenias or systemic features 3
• May represent the initial presentation of SLE, requiring autoantibody screening 3

Vasculitis Syndromes

• Palpable purpura, digital ischemia, or mononeuritis multiplex suggest primary vasculitis rather than SLE 1
• ANCA-associated vasculitides (granulomatosis with polyangiitis, microscopic polyangiitis) have distinct organ involvement patterns 1

Malignancy Considerations

Lymphoproliferative Disorders

• SLE patients have increased risk of non-Hodgkin's lymphoma 3
• Persistent lymphadenopathy, B symptoms, and progressive cytopenias warrant lymph node biopsy 3

Critical Diagnostic Approach

Essential Laboratory Evaluation

• ANA testing is the screening test (96.1% sensitive for SLE) 8, 2
• Anti-dsDNA and anti-Sm antibodies are highly specific for SLE 3, 8, 2
• Low complement levels (C3, C4) indicate active disease and immune complex consumption 3, 7
• Complete blood count identifies cytopenias (anemia, leukopenia, thrombocytopenia) 3, 7
• Urinalysis with microscopy detects proteinuria and cellular casts indicating lupus nephritis 3, 5, 7

Imaging and Tissue Diagnosis

• Renal biopsy is mandatory when proteinuria or active urinary sediment is present to determine lupus nephritis class 5
• Brain MRI should be obtained if neuropsychiatric symptoms develop to exclude structural lesions, ischemia, or infection 3, 7
• Plain radiographs of affected joints help differentiate non-erosive SLE arthritis from erosive RA 3

Common Diagnostic Pitfalls

• Never attribute all symptoms to SLE without excluding infection, especially in immunosuppressed patients 6
• Do not rely on ANA alone—specificity requires anti-dsDNA, anti-Sm, or other SLE-specific antibodies 8, 2
• Avoid delaying renal biopsy when nephritis is suspected, as histologic class determines treatment intensity 5
• Consider drug-induced lupus in any patient on high-risk medications before diagnosing idiopathic SLE 1
• Screen for antiphospholipid antibodies in all SLE patients given the high overlap and thrombotic risk 3, 7