What is the likely diagnosis and recommended work‑up and treatment for a patient with a high antinuclear antibody titer, positive anti‑double‑stranded DNA IgG, and low complement C3?

Systemic Lupus Erythematosus (SLE)

This serological profile—elevated ANA, positive anti-dsDNA IgG, and low C3—is highly specific for systemic lupus erythematosus and warrants immediate comprehensive evaluation for organ involvement, particularly lupus nephritis. 1

Likely Diagnosis

The combination of positive ANA (required entry criterion per EULAR/ACR 2019 classification), positive anti-dsDNA antibodies, and low complement C3 strongly indicates active SLE with probable renal involvement. 1 This serological triad has 97.42% sensitivity and 80.97% specificity for SLE when all three markers are present together. 2

• Low C3 with positive anti-dsDNA has 72-85% sensitivity for active lupus nephritis, making renal involvement highly likely even in the absence of overt symptoms. 1
• The peripheral ANA pattern, if present, correlates with the highest anti-dsDNA levels, lowest C4 levels, and most pathogenic immune profile. 3

Essential Work-Up

Immediate Laboratory Assessment

Complete the following tests urgently to assess disease activity and organ involvement: 1

• Renal function panel: Serum creatinine, estimated GFR, serum albumin 1
• Urinalysis with microscopy: Look for proteinuria, hematuria, cellular casts (>80% sensitivity/specificity for renal flares) 1
• Spot urine protein-to-creatinine ratio (first morning void preferred) 1
• Complete blood count: Assess for cytopenias (anemia, thrombocytopenia, leukopenia/lymphopenia) 1
• Complement C4 level: C4 has 28-74% sensitivity for active lupus nephritis 1
• Anti-ENA panel: Test for anti-Smith, anti-Ro/SSA, anti-La/SSB, anti-RNP antibodies 1
• Antiphospholipid antibodies: Anticardiolipin IgG/IgM, anti-β2-glycoprotein I IgG/IgM, lupus anticoagulant (30-40% of SLE patients are positive) 1
• Total IgG and IgG subclasses (IgG3, IgG4) to assess infection risk 1

Additional Serological Testing

• Anti-C1q antibodies: High negative predictive value for lupus nephritis flares 4
• Anti-nucleosome antibodies: 83.33% sensitivity and 96.67% specificity for SLE when anti-dsDNA is equivocal 1

Organ-Specific Evaluation

If proteinuria or active urinary sediment is present, proceed immediately to renal biopsy to classify lupus nephritis and guide immunosuppressive therapy. 1 Biopsy provides critical prognostic information and determines treatment intensity. 1

Assess for extrarenal manifestations: 1

• Mucocutaneous involvement (malar rash, discoid lesions, photosensitivity)
• Serositis (pleuritis, pericarditis)
• Neuropsychiatric symptoms
• Hematologic abnormalities

Critical Monitoring Considerations

Do NOT repeat ANA testing once positive—this is neither appropriate nor cost-effective for monitoring disease activity. 4 Instead: 1, 4

• Monitor anti-dsDNA quantitatively using the same method and laboratory at each visit 1, 4
• Monitor C3 and C4 levels at every visit, as changes predict concurrent or impending flares better than absolute values 1
• Repeat serological tests no more than monthly 1
• Important caveat: Active serology (decreasing C3/C4 and/or increasing anti-dsDNA) without proteinuria or active urine sediment is NOT an indication for pre-emptive immunosuppressive treatment but mandates closer monitoring. 1

Treatment Approach

Baseline Therapy for All SLE Patients

Hydroxychloroquine 400 mg/day (or 6.5 mg/kg/day, whichever is lower) should be initiated immediately, as it is associated with higher rates of renal response, fewer renal relapses, and reduced damage accrual. 1 Baseline ophthalmological examination is required, with annual screening starting after 5 years. 1

Immunosuppressive Therapy

If lupus nephritis is confirmed on biopsy, initiate aggressive immunosuppression according to the histological class (Class III-V require intensive induction therapy with cyclophosphamide or mycophenolate mofetil plus high-dose corticosteroids). 1

Adjunctive Measures

• RAAS blockade (ACE inhibitors or ARBs) for all patients with significant proteinuria or hypertension, targeting blood pressure <130/80 mmHg 1
• Non-live vaccines per EULAR recommendations (influenza, pneumococcal, hepatitis B) 1
• Sun avoidance, adequate vitamin D and calcium intake, cardiovascular risk reduction 1

Common Pitfalls to Avoid

• Do not delay renal biopsy if there is any evidence of proteinuria or active sediment—early histological diagnosis is critical for preventing irreversible damage. 1
• Do not treat based on serological activity alone (rising anti-dsDNA or falling complement) without clinical evidence of disease activity. 1
• Do not use CRP to monitor SLE activity—significantly elevated CRP (>50 mg/L) suggests superimposed infection rather than lupus flare. 1
• Avoid live vaccines in patients on immunosuppression or corticosteroids >20 mg/day. 1