Complement Inhibitors

Complement inhibitors are targeted immune therapies that block overactivation of the complement cascade.

They are used in diseases driven by complement-mediated tissue injury.

See physiology:

• Complement System

Complement inhibitors act at different levels of the cascade:

• C3 inhibition
• C5 inhibition
• C5a receptor blockade

Blocking complement reduces:

• Hemolysis
• Inflammation
• Membrane attack complex formation

These block cleavage of C5 → prevent:

• C5a (anaphylatoxin)
• C5b-9 (MAC)

Drugs:

• Eculizumab
• Ravulizumab

Indications:

• Paroxysmal nocturnal hemoglobinuria (PNH)
• Atypical hemolytic uremic syndrome (aHUS)
• Generalized myasthenia gravis
• Neuromyelitis optica spectrum disorder

Key risk:

• Increased risk of Neisseria infection

Vaccination required before initiation.

Block upstream C3 activation.

Drug:

• Pegcetacoplan

Effect:

• Prevents opsonization (C3b)
• Prevents downstream C5 activation

Used in:

• Paroxysmal nocturnal hemoglobinuria

Block inflammatory signaling of C5a.

Drug:

• Avacopan

Used in:

• ANCA-associated vasculitis

Mechanism:

Blocks C5a-mediated neutrophil activation without blocking MAC formation.

Complement overactivation contributes to:

• Paroxysmal Nocturnal Hemoglobinuria
• Atypical HUS
• ANCA-Associated Vasculitis
• Neuromyelitis optica

• C5 inhibitors block MAC formation.
• C3 inhibitors block all downstream complement activity.
• C5a receptor inhibitors block inflammation but preserve MAC.
• Major risk: meningococcal infection.
• Vaccinate before starting therapy.