What is the most likely diagnosis in the presence of SSA (Sjögren's syndrome antigen)-52, SSA-60, Smith/RNP (Ribonucleoprotein) antibody, PM/SCL (Polymyositis/Scleroderma) 100 antibody, and ANA (Antinuclear Antibody) positivity?

Most Likely Diagnosis: Systemic Lupus Erythematosus (SLE) with Overlap Features

The combination of SSA-52, SSA-60, Smith/RNP antibody, PM/SCL 100 antibody, and positive ANA most strongly suggests systemic lupus erythematosus (SLE), though the presence of PM/SCL 100 antibody raises consideration of an overlap syndrome with scleroderma features.

Diagnostic Reasoning

Primary Diagnosis: SLE

The antibody profile points most strongly toward SLE based on the following:

• Smith/RNP antibody is one of the most common autoantibody targets in SLE, specifically the spliceosome small nuclear ribonucleoproteins (Smith) and U1-ribonucleoprotein 1
• SSA-60 (anti-Ro60/SSA) antibodies have prognostic value in SLE and are associated with neonatal lupus when present 1
• Positive ANA is a fundamental screening test for SLE, and when combined with anti-ENA antibodies (like Smith/RNP), strongly supports the diagnosis 1
• The combination of Smith antibodies with SSA antibodies is characteristic of SLE rather than isolated Sjögren's syndrome 1

Overlap Syndrome Consideration

The presence of PM/SCL 100 antibody complicates the picture:

• PM/SCL 100 antibodies are specifically associated with systemic sclerosis (scleroderma) and polymyositis overlap syndromes 1
• This antibody is part of the recommended serological panel when systemic sclerosis is suspected, along with anti-Scl-70/topoisomerase-1, anti-centromere, and anti-RNA polymerase III 1
• The presence of both SLE-associated antibodies (Smith/RNP) and scleroderma-associated antibodies (PM/SCL 100) suggests a mixed connective tissue disease or overlap syndrome 1

SSA Antibody Pattern Analysis

The dual positivity for SSA-52 and SSA-60 provides additional diagnostic information:

• SSA-52 (anti-Ro52/TRIM21) combined with SSA-60 (anti-Ro60/SSA) is associated with more severe disease manifestations, including arthritis, inflammation, hypergammaglobulinemia, positive rheumatoid factor, leukopenia, and lymphopenia 2
• While SSA antibodies are strongly associated with Sjögren's syndrome, the presence of Smith antibodies shifts the diagnosis toward SLE 3, 4
• Isolated SSA-60 positivity is more common in SLE (39.47% sole positivity rate), whereas primary Sjögren's syndrome predominantly shows SSA-52 antibodies (93.33% positivity) 4
• The combination of both SSA-52 and SSA-60 with Smith antibodies is more consistent with SLE than primary Sjögren's syndrome 4

Clinical Evaluation Required

To confirm the diagnosis and assess disease severity, evaluate for:

SLE-Specific Features

• Renal involvement: Check serum creatinine, urinalysis, and urine protein/creatinine ratio 1
• Hematologic abnormalities: Complete blood count looking for anemia, thrombocytopenia, leukopenia, or lymphopenia (associated with SSA antibodies) 1, 5
• Complement levels: C3 and C4 levels correlate with disease activity 1
• Anti-dsDNA antibodies: Should be tested as they correlate with disease activity and renal disease 1
• Antiphospholipid antibodies: Test for anticardiolipin, anti-β2GP1, and lupus anticoagulant, as 30-40% of SLE patients are positive 1

Overlap Syndrome Features

• Scleroderma manifestations: Examine for skin thickening, Raynaud's phenomenon, digital ulcers, and telangiectasias (given PM/SCL 100 positivity) 1
• Myositis features: Check creatine phosphokinase, myoglobin, and aldolase levels; assess for proximal muscle weakness 1
• Interstitial lung disease: Obtain high-resolution CT chest and pulmonary function tests, as PM/SCL antibodies are associated with ILD 1, 6

Sjögren's Syndrome Features

• Sicca symptoms: Assess for dry eyes (foreign body sensation, light sensitivity) and dry mouth (need for liquids to swallow, frequent water sipping) 3
• Extraglandular manifestations: Look for vasculitis, purpura, and lymphadenopathy (associated with anti-Ro/SSA antibodies) 5
• Rheumatoid factor: Often positive in patients with SSA antibodies and Sjögren's features 3, 5

Critical Pitfalls to Avoid

• Do not diagnose isolated Sjögren's syndrome in the presence of Smith/RNP antibodies, as this antibody profile is characteristic of SLE 1
• Do not ignore the PM/SCL 100 antibody: This mandates evaluation for scleroderma features and interstitial lung disease, even if SLE is the primary diagnosis 1
• Do not rely solely on ANA positivity: The specific antibody pattern (Smith/RNP, SSA, PM/SCL) provides much more diagnostic information than ANA alone 1
• Monitor for severe disease course: The combination of SSA-52 and SSA-60 antibodies predicts more severe disease with systemic manifestations 2
• Screen for pregnancy complications: If the patient is a woman of childbearing age, SSA antibodies are associated with neonatal lupus and congenital heart block, requiring serial fetal echocardiography and consideration of hydroxychloroquine during pregnancy 6

Disease Severity Indicators

Patients with this antibody profile are at higher risk for:

• Vasculitis and hematologic abnormalities: Anti-Ro/SSA antibodies define a subset with extraglandular disease including vasculitis, purpura, anemia, leukopenia, and thrombocytopenia 5
• Serologic hyperreactivity: Expect hypergammaglobulinemia, positive rheumatoid factor, cryoglobulinemia, and hypocomplementemia 5
• Lymphoma risk: If Sjögren's features are prominent, there is approximately 10% risk of developing lymphoma, with decreased C4 levels indicating higher risk 3