Complement Inhibitors

Complement inhibitors block parts of the complement cascade that damage red cells, endothelium, kidney and nerve in complement-mediated disease.

They treat paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uraemic syndrome (aHUS), generalised myasthenia gravis, neuromyelitis optica spectrum disorder and cold agglutinin disease. Blocking terminal complement leaves patients open to serious infection with encapsulated bacteria, especially Neisseria meningitidis.

Mechanism. Eculizumab and ravulizumab bind C5 and stop formation of the membrane attack complex and C5a. Pegcetacoplan blocks C3, and iptacopan blocks factor B (alternative complement activation); both also reduce extravascular haemolysis. Sutimlimab blocks C1s in cold agglutinin disease.

Pharmacokinetics. Eculizumab half-life about 11 days; ravulizumab about 50 days. Pegcetacoplan is given subcutaneously twice weekly; iptacopan is oral twice daily.

Vaccination and prophylaxis.

• Give meningococcal ACWY and group B vaccines at least 2 weeks before the first dose, and pneumococcal and Haemophilus influenzae type b vaccines.
• If treatment cannot wait, give the vaccine on the same day and cover with antibiotics.
• Give daily antibiotic prophylaxis (penicillin V 500 mg twice daily or equivalent) throughout treatment and for 3 months after the last dose, because vaccines do not give full protection.

Switching. Moving from eculizumab to ravulizumab is done by a loading dose 2 weeks after the last eculizumab dose.

• First-line. PNH with haemolysis or thrombosis; aHUS (early treatment prevents renal loss); AChR antibody positive generalised myasthenia gravis refractory to conventional immunotherapy.
• Alternative. Ravulizumab for fewer infusions; pegcetacoplan or iptacopan when extravascular haemolysis persists on a C5 inhibitor; sutimlimab for cold agglutinin disease with haemolysis.
• Specialist. Neuromyelitis optica spectrum disorder, C3 glomerulopathy, thrombotic microangiopathy after transplant.
• Emergency. aHUS with acute kidney injury, after plasma exchange has started and while diagnosis is being completed.

Selection. Confirm PNH with flow cytometry and aHUS after excluding thrombotic thrombocytopenic purpura (ADAMTS13) and Shiga toxin haemolytic uraemic syndrome. Choose by indication, availability, infusion burden and cost.

Contraindications. Unresolved Neisseria meningitidis infection; no meningococcal vaccination and no antibiotic prophylaxis; hypersensitivity. Pegcetacoplan: unvaccinated for encapsulated organisms.

Serious adverse effects.

• Meningococcal sepsis and other encapsulated infection (fatal if delayed).
• Infusion reactions, headache, nausea, upper respiratory infection.
• Breakthrough haemolysis at the end of a dosing interval or after missing doses.
• Injection-site reactions and haemolysis if pegcetacoplan is missed.

Major interactions. Few. Immunosuppressants add infection risk. Plasma exchange and IVIG remove eculizumab, so a supplemental dose is needed after exchange.

Common prescribing errors.

• Starting without vaccination or antibiotic cover.
• Missing or delaying maintenance doses.
• Not giving a supplemental dose after plasma exchange.
• Mistaking fever for minor illness (any fever needs urgent review).
• Stopping treatment in aHUS without monitoring for relapse.

Special groups.

• Pregnancy: eculizumab is used in PNH and aHUS in pregnancy with specialist care; ravulizumab data are limited.
• Breastfeeding: low transfer; specialist advice.
• Children: weight-based dosing for eculizumab and ravulizumab.
• Older adults: no adjustment.
• Kidney and liver: no adjustment.
• East Africa: meningococcal disease is endemic in parts of the meningitis belt, so vaccination and prophylaxis are essential; access and cost are very limited, and treatment normally depends on specialist programmes.

Monitoring. Lactate dehydrogenase, haemoglobin, reticulocytes and haptoglobin for PNH; platelets, creatinine and haemolysis markers for aHUS; infection symptoms at every contact; complement activity where available; patient safety card.

Referral and escalation. Fever, headache with neck stiffness or rash (immediate antibiotics and hospital care); breakthrough haemolysis; thrombosis; renal decline; planned pregnancy.

Comparison with alternative classes. Complement inhibitors are the only disease-modifying option for PNH and aHUS and cut transfusion and thrombosis, but cost very much and need lifelong prophylaxis. Transfusion, steroids and plasma exchange are supportive alternatives.