Does glucocorticoid therapy change serum complement component 3 (C3) and complement component 4 (C4) levels?

Effect of Glucocorticoid Therapy on Serum C3 and C4 Complement Levels

Glucocorticoid therapy reduces complement activation and lowers C3d levels acutely, but does not significantly alter total serum C3 or C4 concentrations in most clinical contexts.

Acute Effects on Complement Activation

The most robust evidence comes from rheumatoid arthritis patients, where glucocorticoids demonstrate a clear anti-inflammatory effect on the complement system:

• Prednisolone 30 mg daily causes a rapid 67% reduction in plasma C3d (a marker of complement activation) within the first 48 hours of treatment in patients with active rheumatoid arthritis 1
• This reduction in C3d reflects decreased complement activation rather than changes in total complement protein synthesis 1
• Total serum C3 and C4 levels remain unchanged despite the marked reduction in complement activation products during the first 2 weeks of steroid therapy 1

Lack of Effect on Total Complement Levels

Multiple lines of evidence confirm that glucocorticoids do not meaningfully alter baseline complement component concentrations:

• In septic shock patients receiving corticosteroids, C3, C4, and Factor B levels were not altered by steroid administration, even in the setting of severe systemic inflammation 2
• The stability of total C3 and C4 contrasts sharply with the rapid decline in activation markers like C3d, indicating that steroids suppress complement pathway activation without changing the circulating pool of complement proteins 1

Clinical Context: Complement-Mediated Glomerular Disease

In the specific setting of C3 glomerulopathy and complement-driven kidney disease, the relationship becomes more nuanced:

• Glucocorticoids combined with mycophenolate mofetil are recommended as initial therapy for moderate-to-severe C3 glomerulopathy, despite the lack of direct effect on C3/C4 levels 3
• The therapeutic benefit in these conditions likely derives from broader immunosuppressive effects rather than direct modulation of complement protein concentrations 4
• Glucocorticoids are of little benefit in established C3 glomerulopathy and their efficacy depends heavily on disease timing and severity 4

Mechanism of Action

The disconnect between complement activation and total protein levels reflects the dual mechanism of glucocorticoid action:

• Glucocorticoids suppress inflammatory transcription factors and reduce complement pathway activation through transrepression mechanisms 4
• They do not directly inhibit hepatic synthesis of complement proteins, explaining why C3 and C4 concentrations remain stable 1
• The reduction in C3d (activation product) without change in C3 (total protein) demonstrates that steroids block complement consumption rather than production 1

Monitoring Implications

For patients on chronic glucocorticoid therapy:

• Serial C3 and C4 measurements are not useful markers of steroid effect or compliance, as these values do not change with treatment 1, 2
• If monitoring complement activity is clinically indicated, measure activation products (C3d, C5a) rather than total C3/C4 levels 1
• Standard glucocorticoid monitoring should focus on glucose, blood pressure, lipids, and bone density rather than complement levels 3, 5

Common Pitfalls

• Do not interpret stable C3/C4 levels as evidence of treatment failure in complement-mediated diseases—the therapeutic effect occurs through reduced activation, not altered protein concentrations 1
• Avoid using C3/C4 trends to guide glucocorticoid dosing decisions, as these parameters remain unchanged regardless of dose or duration 1, 2
• In vasculitis and glomerulonephritis, disease activity should be assessed through clinical parameters, proteinuria, and renal function rather than complement levels during steroid therapy 3