Why do patients with Systemic Lupus Erythematosus (SLE) typically have low Complement 3 (C3) and Complement 4 (C4) levels?

Why SLE Patients Have Low C3 and C4 Levels

Patients with SLE have low C3 and C4 levels primarily due to increased consumption of complement proteins through immune complex-mediated activation of the classical complement pathway, which serves as both a pathogenic mechanism and an important biomarker of disease activity. 1

Primary Mechanism: Immune Complex-Mediated Consumption

• The classical complement pathway is activated by immune complexes formed between autoantibodies (particularly anti-dsDNA antibodies) and their target antigens, leading to sequential consumption of C1q, C4, and C3 components 2

• Active complement consumption generates anaphylatoxins C3a and C5a, which circulate at elevated levels during disease exacerbations (mean C3a: 526 ng/ml in severe disease vs. 134 ng/ml in controls; mean C5a: 46.0 ng/ml vs. 17.1 ng/ml in controls), demonstrating ongoing complement activation even when C3/C4 levels are depleted 3

• Complement levels represent an important biomarker of SLE activity, with low C3 and C4 indicating active disease and higher consumption rates 4

Clinical Patterns of Complement Consumption

Classical Pathway Activation (Low C3 AND C4)

• Patients with both low C3 and C4 have higher frequencies of major organ involvement, including:

  • Arthritis: 50.0% vs. 13.0% in alternative pathway activation 5
  • Serositis: 37.5% vs. 13.0% 5
  • Nephritis: 63.6% vs. 21.7% 5
  • Anti-dsDNA antibodies: 73.9% vs. 30.4% 5

• This pattern reflects immune complex deposition activating the full classical complement cascade 5

Alternative Pathway Activation (Low C3, Normal C4)

• Some SLE patients show isolated C3 consumption with normal C4, indicating alternative pathway activation 5

• This pattern is associated with antiphospholipid antibodies (70.6% vs. 37.3%) and antiphospholipid syndrome (39.1% vs. 5.7%), suggesting a different pathogenic mechanism 5

Special Considerations with Antiphospholipid Antibodies

• aPL-positive SLE patients have significantly lower complement levels compared to aPL-negative patients (median C3: 0.92 vs. 1.07 g/l, p=0.001; median C4: 0.11 vs. 0.16 g/l, p<0.0001) 6

• This reflects more pronounced complement activation and higher consumption rates in aPL-positive disease 6

Paradoxical Role of Complement Deficiency

• Genetic deficiencies of early classical pathway components (C1q, C1r, C1s, C4, C2) are paradoxically strong risk factors for developing SLE, with homozygous deficiencies strongly associated with lupus development 2

• Low copy numbers of C4A represent medium to large effect size risk factors for SLE in European and East-Asian populations, while high copy numbers are protective 2

• This paradox occurs because complement deficiency impairs clearance of immune complexes and apoptotic debris, leading to autoantigen exposure and autoantibody production 2

Clinical Monitoring Implications

• C3 and C4 levels should be assessed as part of initial diagnostic evaluation and monitored regularly 1

• Patients with established nephropathy require monitoring of C3 and C4 every 3 months for the first 2-3 years alongside proteinuria and anti-dsDNA antibodies 1

• Complement levels may be more sensitive than traditional markers: C3a was elevated in 15 of 21 patients with active SLE, whereas low C3 or C4 was noted in only 7 of these 21 patients 3

Common Pitfall to Avoid

• Do not assume normal C3/C4 levels exclude active disease - complement activation products (C3a, C5a) may be elevated even when static complement levels appear normal, and some patients activate primarily through the alternative pathway with isolated C3 consumption 3, 5