Complement C4 and C5 Levels: Critical Disorders for Monitoring
Complement C4 levels are most important in systemic lupus erythematosus (SLE), where they serve as biomarkers of disease activity and predict renal involvement, while C5 activation products indicate acute disease exacerbations and vascular injury. 1, 2
Primary Clinical Applications
Systemic Lupus Erythematosus (SLE)
C4 monitoring is essential in SLE for assessing disease activity and guiding treatment decisions. 1
- Low C4 levels correlate with active disease, particularly lupus nephritis, though they lack predictive value for disease flares 1
- C4 should be measured alongside C3 at initial assessment and during follow-up visits, especially in patients on immunosuppressive therapy 1
- In lupus nephritis specifically, C4 levels combined with age, ethnicity, serum creatinine, and hypertension predict 5-year renal survival 1
- C4d (the activation product of C4) is more sensitive than total C4 for detecting moderate-to-severe disease activity 3
- Erythrocyte-bound C4d (EC4d) and B cell-bound C4d (BC4d) better correlate with disease activity than plasma C4 levels alone 4
C5a anaphylatoxin levels are elevated during acute SLE exacerbations and may contribute to vascular injury. 2
- Mean C5a concentration in acutely ill SLE patients reaches 46.0 ng/ml versus 17.1 ng/ml in controls (p<0.01) 2
- C5a measurement may be useful for managing patients with severe disease activity 2
- C5b-9 (membrane attack complex) can be measured but is less sensitive than C4d for predicting disease activity 3
Complement-Mediated Glomerular Diseases
C4 glomerulopathy (C4G) represents a distinct disease entity requiring complement system evaluation. 1
- When kidney biopsy shows a complement-dominant pattern with C4 deposition, comprehensive complement workup is mandatory 1
- C4G must be distinguished from immune complex glomerulonephritis and C3 glomerulopathy, as each requires different therapeutic approaches 1
- Immunofluorescence showing C4 without immunoglobulins indicates primary complement dysregulation 1
Primary Immunodeficiency Disorders
Early classical complement pathway deficiencies (including C4) present with either lupus-like autoimmune disease or recurrent bacterial respiratory infections. 1
- C4 deficiency specifically predisposes to SLE-like syndromes 1
- Terminal complement component deficiencies (C5-C9) cause recurrent neisserial meningitis 1
- No specific therapy exists for complement deficiency; management relies on antibiotic prophylaxis and immunization 1
Monitoring Strategy in SLE
Serial C3 and C4 measurements should be obtained every 3 months in active SLE to monitor disease activity and treatment response. 5
- Complement levels should be checked alongside anti-dsDNA antibodies 1, 5
- Patients with high disease activity (anti-dsDNA >300 IU/mL, positive anti-Sm, and low complements) require aggressive immunosuppression 5
- Testing for anti-C1q antibodies should be considered when available, as they correlate with lupus nephritis 1
Important Clinical Caveats
Normal C3 and C4 levels do not exclude active SLE. 6, 3
- In one study, only 7 of 21 patients with active SLE had low C3 or C4, while 15 of 21 had elevated C3a 2
- Complement activation products (C4d, C3a, C5a) are more sensitive than total complement levels for detecting disease activity 4, 3
- Some patients maintain normal complement levels despite clinical disease activity due to increased hepatic synthesis 6
C4 levels can decrease post-vaccination in SLE patients, which does not necessarily indicate disease flare. 1
- One study showed C4 decreased from 0.24 g/L to 0.20 g/L (p=0.004) 13 days after pneumococcal vaccination 1
- This represents transient complement consumption rather than disease activation 1
Additional Disorders
Antiphospholipid syndrome (with or without SLE) shows elevated platelet-bound C4d (PC4d) correlating with thrombosis risk. 4