What is the role of the complement system in disease and how is it managed, particularly in conditions like atypical hemolytic uremic syndrome (aHUS) with medications such as eculizumab (eculizumab is a monoclonal antibody that inhibits the complement protein C5)?

The Complement System in Disease and Management

Overview of the Complement System

The complement system is a cascade of over 50 proteins that forms an essential component of innate immunity, but when dysregulated or overactivated, it becomes the primary pathogenic mechanism in several critical diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy, and contributes significantly to conditions like sepsis, ARDS, and severe COVID-19. 1

The system functions through organized proteolytic cascades that, when excessive, contribute to tissue damage, runaway inflammation, and capillary leakage syndrome. 1

Complement-Mediated Diseases and Their Management

Atypical Hemolytic Uremic Syndrome (aHUS)

For patients with aHUS, eculizumab should be initiated within hours of diagnosis to prevent increased morbidity and mortality, as treatment delays are directly associated with worse outcomes. 2

Mechanism and Pathophysiology

• aHUS results from dysregulation of the alternative complement pathway, leading to thrombotic microangiopathy with glomerular endothelial injury rather than discrete glomerular deposits. 3
• Germline mutations in complement proteins or their regulators fail to protect the glomerular endothelium from complement activation, resulting in thrombotic microangiopathy and renal failure. 4

Eculizumab Treatment Protocol

• Eculizumab is a humanized monoclonal IgG2/4κ antibody that specifically binds complement protein C5 with high affinity, preventing its cleavage to C5a and C5b, thereby blocking formation of the terminal complement complex C5b-9. 5
• The drug inhibits terminal complement-mediated thrombotic microangiopathy in aHUS patients. 5
• For aHUS, the maintenance dose is 1200 mg intravenously every 2 weeks, achieving a mean trough concentration of 242 ± 101 mcg/mL at week 26. 5
• Steady state is achieved 4 weeks after starting treatment, with a half-life of approximately 270-414 hours. 5
• Free C5 concentrations <0.5 mcg/mL correlate with complete blockade of terminal complement activity. 5

Critical Safety Requirements

Mandatory infection prevention measures must be implemented before or immediately upon initiating eculizumab: 2

• Quadrivalent meningococcal conjugate vaccine 2
• Meningococcal B vaccine 2
• Long-term antimicrobial prophylaxis with penicillin 2
• Vaccinations for Streptococcus pneumoniae and Haemophilus influenzae type b according to ACIP guidelines 5

The main adverse event is Neisseria infection, which is rare but can be fatal if not prevented. 1

Clinical Efficacy

• Eculizumab has been proven effective and safe in clinical trials for aHUS, with dramatic improvement in hematological parameters and renal function. 6, 4
• Long-term treatment (>24 months) shows sustained disease control with improved renal function, resolution of proteinuria, and substantially improved quality of life. 7
• Renal biopsy after 2 months of eculizumab therapy demonstrates absence of thrombotic microangiopathy, confirming inhibition of the terminal complement pathway. 7
• The safety and effectiveness of eculizumab for aHUS appear similar in pediatric (ages 2 months to 17 years) and adult patients. 5

Special Considerations

• For patients receiving plasma exchange or infusion, supplemental eculizumab dosing is required, as these procedures increase clearance by approximately 250-fold and reduce half-life to 1.26 hours. 5
• When renal transplantation is required, eculizumab can be used prophylactically to prevent aHUS recurrence. 1
• Eculizumab may be effective in drug-induced HUS (such as mitomycin-C-induced) that is unresponsive to plasma exchanges. 6

C3 Glomerulopathy

For patients with C3 glomerulopathy without monoclonal gammopathy and moderate-to-severe disease, initial treatment should be mycophenolate mofetil (MMF) plus glucocorticoids, with eculizumab considered only if this first-line therapy fails. 3, 8

Diagnostic Approach

• C3 glomerulopathy encompasses C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), characterized by discrete deposits of C3 in the glomerulus due to complement dysregulation. 3
• Before diagnosing primary C3G, active or prior infections must be excluded, as infections can trigger complement abnormalities in genetically susceptible patients. 8, 9
• Comprehensive evaluation should include screening for infections, autoimmune diseases, and monoclonal gammopathies. 8
• For all adult patients with C3G, especially those over 50 years old, serum and urine immunoelectrophoresis, immunofixation, and serum free light chain analysis must be performed, as 60-80% of these patients have a monoclonal gammopathy at diagnosis. 8, 9
• Specialized complement testing should be performed even in the absence of hypocomplementemia. 9

Treatment Algorithm by Disease Severity

Mild Disease:

• Supportive therapy with RAS inhibition alone is recommended. 9
• Immunosuppression should be avoided in this population. 9

Moderate Disease:

• First-line treatment with a limited course of glucocorticoids. 9
• If contraindications to glucocorticoids exist, consider mycophenolate mofetil, rituximab, or cyclophosphamide. 9
• Avoid calcineurin inhibitors, as long-term use is associated with immune complex-negative angiopathy and thrombotic microangiopathy. 9

Moderate-to-Severe Disease:

• Initial treatment with MMF plus glucocorticoids. 3, 8
• If this fails, eculizumab should be considered. 3, 8

Crescentic C3G with Rapidly Progressive Glomerulonephritis:

• Treatment with high-dose glucocorticoids and cyclophosphamide may be considered, similar to ANCA-associated vasculitis protocols. 8

Special Considerations for Monoclonal Gammopathy

• When monoclonal gammopathy is present, treatment should focus on controlling the clone of B cells or plasma cells responsible for monoclonal immunoglobulin production rather than complement inhibition. 3, 8
• Hematology consultation should be obtained for management of the underlying plasma cell or B cell disorder. 8
• Pronase digestion on paraffin-embedded biopsy tissue should be performed in all cases of apparent C3G with circulating monoclonal immunoglobulin to detect masked monoclonal immunoglobulin deposits that may be missed during routine immunofluorescence. 3, 9

Eculizumab in C3 Glomerulopathy

• Eculizumab has been used in a small number of C3G patients with variable results. 3
• Many newer medications are under investigation that block the alternative pathway at specific sites (complement factor inhibitors or "-copans"), which may provide more targeted therapy than eculizumab's final common pathway blockade. 3
• All patients with C3GN, not only those refractory to initial therapy, should be considered for clinical trial participation when feasible, given the paucity of evidence for treating this condition. 3

Catastrophic Antiphospholipid Syndrome

• Catastrophic APS is characterized by rapid-onset thrombosis affecting multiple organs with high mortality. 3
• Complement activation is involved in the pathogenesis of tissue injury induced by antiphospholipid antibodies, and there is emerging evidence on the efficacy of eculizumab in treating catastrophic APS. 3
• Treatment includes glucocorticoids, and plasma exchange is often used with improved patient survival in retrospective studies. 3

Monitoring Eculizumab Therapy

The Wieslab® complement screen assay demonstrates sensitivity of 1-2% of C5 activity and can reliably monitor complete blockade of terminal complement pathway activity for up to four weeks after eculizumab infusion. 10

• Patient samples obtained during treatment show complete blockade of terminal complement pathway activity for up to four weeks after infusion. 10
• Levels of eculizumab-C5 complexes are inversely correlated to complement activity. 10
• Titrating serum from eculizumab-treated patients into normal serum reveals that eculizumab is present in excess up to four weeks after infusion. 10
• These assays can be used to design individual eculizumab dosage regimens. 10

Common Pitfalls and Caveats

Critical Diagnostic Errors to Avoid:

• Failure to screen for monoclonal gammopathy, especially in patients over 50 years old with C3G, may lead to inappropriate treatment selection. 8
• Diagnosing primary C3G without excluding infection-related or post-infectious glomerulonephritis. 8
• Not performing pronase digestion in cases of apparent C3G with circulating monoclonal immunoglobulin, potentially missing masked monoclonal deposits. 9
• Approximately 5-10% of patients with monoclonal gammopathy and findings consistent with C3G on standard immunofluorescence may actually have membranoproliferative glomerulonephritis with masked monoclonal deposits. 9

Treatment Pitfalls:

• Delaying eculizumab initiation in aHUS, as delays are directly associated with increased morbidity and mortality. 2
• Failing to implement mandatory infection prevention measures (meningococcal vaccination and antibiotic prophylaxis) before or immediately upon starting eculizumab. 2, 5
• Using eculizumab as first-line therapy for C3G before trying MMF plus glucocorticoids. 3, 8
• Not adjusting eculizumab dosing in patients receiving plasma exchange or infusion. 5