What is the most likely diagnosis in a patient with a positive antinuclear antibody screen, positive anti‑double‑stranded DNA antibody, elevated C‑reactive protein, normal complement C3 level, and an erythrocyte sedimentation rate of 22 mm/hr?

Diagnosis: Systemic Lupus Erythematosus (SLE)

The combination of positive ANA screen, positive anti-double-stranded DNA antibody, elevated C-reactive protein (13.1 mg/L), normal complement C3 (204 mg/dL), and ESR of 22 mm/hr is most consistent with systemic lupus erythematosus, likely with active inflammatory arthritis rather than active nephritis. 1, 2, 3

Interpretation of Laboratory Findings

Autoantibody Profile

• Positive ANA and anti-dsDNA antibodies together have 95-97% specificity for SLE, making this the cornerstone of diagnosis 3, 4
• The anti-dsDNA antibody is a hallmark of SLE and typically correlates with disease activity, though its absence does not exclude lupus nephritis 5
• When both ANA and anti-dsDNA are positive using quantitative methods, the positive predictive value approaches 96-100% for SLE 3, 4

Inflammatory Markers Pattern

• The elevated CRP (13.1 mg/L, normal <5 mg/L) with only mildly elevated ESR (22 mm/hr) suggests active inflammatory arthritis rather than nephritis 6
• In SLE patients with active nephritis, CRP typically remains low or normal despite active disease—a "muted CRP response"—while complement levels drop significantly 6
• Conversely, SLE patients with arthritis characteristically show elevated CRP (median 10 mg/L) and ESR (median 34 mm/h) 6

Complement Analysis

• The normal C3 level (204 mg/dL, normal range typically 90-180 mg/dL) argues strongly against active lupus nephritis 6
• Active nephritis in SLE is characterized by significantly depressed complement C3 (median 73 mg/dL) and C4 levels 6
• Normal complement with positive anti-dsDNA suggests either early disease, limited organ involvement, or predominantly musculoskeletal manifestations 1, 6

Clinical Implications and Next Steps

Immediate Serologic Workup Required

• Complete the autoantibody panel: anti-Sm, anti-SSA/Ro, anti-SSB/La, anti-RNP, rheumatoid factor, and anti-CCP antibodies 1, 2
• Measure complement C4 and CH50 to complete the complement profile 1, 2
• Obtain complete blood count to assess for cytopenias (anemia, leukopenia, thrombocytopenia), which occur in 48-89% of SLE patients 7
• Check comprehensive metabolic panel, particularly serum creatinine and albumin 1, 2

Renal Assessment (Despite Normal C3)

• Obtain urinalysis with microscopy and urine protein-to-creatinine ratio immediately—lupus nephritis can occur even with normal complement in rare cases 1, 2, 5
• Proteinuria, microscopic hematuria, or red cell casts would indicate nephritis requiring urgent rheumatology referral 7
• Calculate estimated glomerular filtration rate (eGFR) as baseline 1, 2

Pulmonary Screening

• Obtain high-resolution chest CT to screen for interstitial lung disease, which occurs in 26% of patients with positive anti-RNP antibodies (if present) 1
• Perform baseline pulmonary function tests with DLCO 7, 1
• Consider echocardiogram if dyspnea is present to evaluate for pulmonary hypertension 7, 1

Infection Screening Before Treatment

• Screen for HIV, hepatitis B and C based on risk factors before initiating immunosuppression 1
• Perform tuberculosis testing according to local guidelines 1
• These tests are mandatory before starting disease-modifying therapy 1

Common Pitfalls to Avoid

Do Not Delay Diagnosis Based on Single Normal Value

• Normal complement does not exclude SLE—approximately 13-27% of SLE patients maintain normal C3/C4 levels even during active disease 6
• The combination of positive ANA plus positive anti-dsDNA is sufficient for diagnosis when clinical features are present 3, 4

Recognize the Arthritis vs. Nephritis Pattern

• Elevated CRP with normal complement points to arthritis, not nephritis 6
• If nephritis were present, you would expect low C3 (median 73 mg/dL), low C4 (median 10 mg/dL), and paradoxically low or normal CRP 6
• This distinction is critical because it determines urgency of treatment and prognosis 6

Anti-dsDNA Testing Method Matters

• Ensure anti-dsDNA was measured by Farr assay or Crithidia luciliae immunofluorescence test (CLIFT), which offer the highest specificity (98-99%) 2, 4
• ELISA methods alone have lower specificity and higher false-positive rates 4
• Combining two quantitative methods (e.g., RIA + CLIA) in patients with homogeneous or speckled ANA pattern maximizes specificity to 100% 4

Prognosis and Monitoring

Disease Activity Correlation

• Anti-dsDNA antibody levels correlate with disease activity, and a rate of increase >1 IU/mL per year is highly specific for progression to proliferative lupus nephritis 8
• Serial anti-dsDNA monitoring can predict future nephritis—elevated levels typically precede clinical nephritis by months to years 8
• ESR and CRP positively correlate with disease activity scores (ρ = 0.23 and 0.19, respectively) 6

Immediate Rheumatology Referral

• All patients with positive anti-dsDNA antibodies require immediate rheumatology referral given the risk of organ involvement and need for disease-modifying therapy 1
• Establish follow-up every 3-6 months initially, extending to every 6-12 months once disease stabilizes 1, 2
• Initiate hydroxychloroquine 200-400 mg daily early, as it benefits multiple organ systems and reduces flare risk 1