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Constitutional C4 Deficiency SLE — SCE Rheumatology MCQ

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HardAutoimmune SerologyConstitutional C4 Deficiency SLESCE Rheumatology

A 50-year-old woman with anti-Ro-positive systemic lupus erythematosus has been clinically quiescent for 18 months. Urinalysis, urine protein:creatinine ratio and renal function remain normal, and her anti-dsDNA titre is unchanged. On repeated testing, C3 is normal but C4 remains between 0.08 and 0.10 g/L. Which complement abnormality is the most likely explanation for this pattern?

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Correct answer: C — Constitutional low C4A gene copy number or a non-expressed C4A allele

The best answer is C. C4 concentration is influenced by C4A and C4B gene copy number; low C4A copy number or a non-expressed allele can produce a constitutively low baseline C4 despite clinically quiescent SLE. Low C4A copy number also has a recognised association with anti-Ro/SSA autoantibodies. Persistent isolated low C4 should therefore not, by itself, trigger escalation of immunosuppression. Occult active SLE would be less likely given prolonged clinical stability, normal renal assessment, stable anti-dsDNA and normal C3. Acquired C1-inhibitor deficiency can lower C4 but usually presents with angioedema. C2 deficiency does not explain a constitutively low C4 concentration, while factor H deficiency predominantly causes alternative-pathway activation with low C3. Serial baseline assessment and, where the distinction would alter management, C4 copy-number analysis can clarify the cause.

Reference: Margery-Muir AA et al. Establishment of gene copy number-specific normal ranges for serum C4 and its utility for interpretation in patients with chronically low serum C4 concentrations. Arthritis & Rheumatology. 2014;66:2512-2520. https://pubmed.ncbi.nlm.nih.gov/24757030/