What diseases are caused by an overactive complement system and how are they managed?

Diseases Caused by Overactive Complement System

An overactive complement system causes several serious diseases including C3 glomerulopathy, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria, which require targeted therapies like mycophenolate mofetil plus glucocorticoids or complement inhibitors like eculizumab to prevent significant morbidity and mortality. 1, 2

Primary Complement-Mediated Diseases

C3 Glomerulopathy (C3G)

• Pathophysiology: Results from dysregulation of the alternative complement pathway causing C3 deposition in glomeruli
• Subtypes:
  • C3 Glomerulonephritis (C3GN)
  • Dense Deposit Disease (DDD)
  • C4 Glomerulopathy (C4G) - related variant
• Clinical presentation: Proteinuria, hematuria, hypertension, progressive kidney dysfunction
• Management:
  1. In patients ≥50 years, evaluate for monoclonal gammopathy 1
  2. For moderate-to-severe disease without monoclonal gammopathy: Mycophenolate mofetil (MMF) plus glucocorticoids 1
  3. For treatment failures: Consider eculizumab (terminal complement inhibitor) 1
  4. Clinical trials should be considered for all patients when available 1

Atypical Hemolytic Uremic Syndrome (aHUS)

• Pathophysiology: Excessive complement activation on endothelial surfaces causing thrombotic microangiopathy 3
• Genetic basis: Mutations in complement regulatory proteins (CFH, MCP, CFI, CFHR5)
• Clinical presentation: Microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury
• Management:
  • Complement inhibitors (eculizumab or ravulizumab) are first-line therapy 2
  • Prophylactic use before kidney transplantation to prevent recurrence 2

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Pathophysiology: Somatic mutations in PIG-A gene leading to deficiency of GPI-anchored complement regulators
• Clinical presentation: Intravascular hemolysis, thrombosis, bone marrow failure
• Management: Terminal complement inhibition with eculizumab or ravulizumab 4

Secondary Complement-Mediated Diseases

Membranoproliferative Glomerulonephritis (MPGN)

• Pathophysiology: Histologic pattern resulting from immune complex deposition and/or complement dysregulation 1
• Classification:
  1. Immunoglobulin/immune complex-mediated:
     • Infection-associated: HCV, HBV, endocarditis, infected shunts
     • Autoimmune disease-associated: SLE, Sjögren's syndrome, rheumatoid arthritis
     • Monoclonal gammopathy-associated
  2. Complement-mediated: C3G, C4G
• Management:
  • Treat underlying cause (infection, autoimmune disease, monoclonal gammopathy)
  • For idiopathic ICGN with proteinuria <3.5g/day: RAS inhibition 1
  • For idiopathic ICGN with nephrotic syndrome: Limited course of glucocorticoids 1

Age-Related Macular Degeneration (AMD)

• Pathophysiology: Polymorphisms in complement genes leading to excessive activation on retinal debris 3
• Clinical presentation: Progressive central vision loss
• Management: Complement inhibitors under investigation 5

Diagnostic Approach

1. Kidney biopsy with immunofluorescence to distinguish:

   • Immunoglobulin-positive patterns (suggesting immune complex disease)
   • Complement-dominant patterns (suggesting C3G or C4G)
   • Negative immunofluorescence (suggesting thrombotic microangiopathy) 1

2. Complement evaluation:

   • Serum C3, C4 levels
   • Specialized tests: Alternative pathway functional assays, complement regulatory protein levels, genetic testing 1

3. Rule out secondary causes:

   • Infections (viral hepatitis, endocarditis, other chronic infections)
   • Autoimmune diseases (SLE, rheumatoid arthritis)
   • Monoclonal gammopathies (especially in patients ≥50 years) 1

Treatment Considerations

• Infection-associated: Treat underlying infection 1
• Autoimmune-associated: Immunosuppression 1
• Monoclonal gammopathy-associated: Target the B-cell or plasma cell clone 1
• Primary complement dysregulation: Complement inhibitors 2

Complement Inhibitors

• Eculizumab/Ravulizumab: Terminal complement inhibitors (anti-C5)
• Emerging therapies: Factor B inhibitors (like LNP023) 5
• Key adverse effect: Increased risk of Neisseria infections requiring vaccination 2

Clinical Pitfalls to Avoid

1. Delayed diagnosis: Don't wait for kidney biopsy results to initiate treatment in rapidly deteriorating patients with suspected ANCA-associated vasculitis 1

2. Incomplete evaluation: Always evaluate for complement dysregulation in cases of idiopathic immune complex glomerulonephritis 1

3. Missing monoclonal proteins: Consider specialized techniques (proteolytic digestion) to detect masked monoclonal immunoglobulins 1

4. Overlooking infections: Rule out infection-related GN before diagnosing C3G 1

5. Inadequate complement testing: Many specialized complement tests require specific collection methods and specialized laboratories 1