Rituximab

Rituximab is a chimeric monoclonal IgG1 antibody to CD20 that depletes B cells. It is used in rheumatoid arthritis, ANCA-associated vasculitis, pemphigus vulgaris, and off label in systemic lupus erythematosus, lupus nephritis, immune thrombocytopenia, autoimmune haemolytic anaemia, membranous nephropathy, nephrotic syndrome, myasthenia gravis and several other immune diseases, and in B cell malignancy. Biosimilar versions are widely used and are not distinguished here.

Class. Anti-CD20 monoclonal antibody, B cell depleting agent.

Mechanism. Binds CD20 on pre-B and mature B cells and causes depletion by complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and apoptosis. Plasma cells lack CD20, so existing antibody titres fall slowly.

Pharmacokinetics. Intravenous only. Half-life about 18 to 22 days, longer with repeated doses. B cell depletion persists for 6 to 12 months or more. Clearance is higher with nephrotic range proteinuria (urinary loss).

Rheumatoid arthritis (with methotrexate).

• 1000 mg intravenously on days 1 and 15.

• Repeat every 24 weeks or as clinical need directs, but not sooner than every 16 weeks.

• Premedication: methylprednisolone 100 mg intravenously 30 minutes before each infusion, with paracetamol and an antihistamine.

ANCA vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis), induction. 375 mg/m2 intravenously once weekly for 4 weeks, or 1000 mg on days 1 and 15, with a glucocorticoid taper.

ANCA vasculitis, maintenance. 500 mg intravenously on days 1 and 15, then 500 mg every 6 months for at least 18 months.

Pemphigus vulgaris. 1000 mg intravenously on days 1 and 15, then 500 mg at month 12 and every 6 months as needed, with a glucocorticoid taper.

Lupus nephritis and refractory systemic lupus erythematosus (off label, specialist). 1000 mg intravenously on days 1 and 15, repeated at 6 months if needed, with a glucocorticoid and a second immunosuppressant.

Immune thrombocytopenia (off label, specialist). 375 mg/m2 weekly for 4 weeks, or 1000 mg on days 1 and 15.

Maximum dose. 1000 mg for each infusion in rheumatological use. Haematological malignancy regimens use different doses and are not covered here.

Infusion rate. First infusion: 50 mg/hour, increase by 50 mg/hour every 30 minutes to a maximum of 400 mg/hour. Later infusions: start at 100 mg/hour and increase by 100 mg/hour every 30 minutes to a maximum of 400 mg/hour.

Contraindications. Severe active infection, severe immunocompromise, hypersensitivity to murine proteins, and severe heart failure (for the rheumatological regimens).

Boxed-warning-level risks. Fatal infusion reactions, severe mucocutaneous reactions, hepatitis B virus reactivation (fulminant hepatitis and death) and progressive multifocal leukoencephalopathy.

Adverse effects. Common: infusion reactions, upper respiratory infection, nausea, headache, rash, arthralgia. Serious: hepatitis B reactivation, progressive multifocal leukoencephalopathy, hypogammaglobulinaemia, late-onset neutropenia, Pneumocystis pneumonia, severe skin reactions, bowel obstruction or perforation, cardiac arrhythmia, tumour lysis in high-burden malignancy.

Major interactions. Live vaccines (avoid); antihypertensives (withhold 12 hours before infusion); other biologics and immunosuppressants add infection risk; cisplatin (renal toxicity in malignancy regimens).

Common prescribing errors. Not screening for hepatitis B surface antigen and core antibody before the first dose; omitting methylprednisolone premedication; vaccinating late (response is blunted for 6 months or more); no Pneumocystis prophylaxis when combined with high dose glucocorticoid or cyclophosphamide.

Special groups.

• Pregnancy: avoid; contraception during treatment and for 12 months after the last dose. Delay live vaccines in infants of exposed pregnancies until B cell counts are normal.

• Breastfeeding: avoid during treatment and for 6 months afterwards.

• Children: used in nephrotic syndrome and vasculitis by specialists, with weight or body surface area dosing.

• Older adults: higher infection risk; check cardiac status.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment; screen for hepatitis B.

• Region: hepatitis B, tuberculosis and HIV are common in East Africa; test before the first dose and give antiviral prophylaxis for hepatitis B core antibody positive patients (entecavir 0.5 mg daily or tenofovir disoproxil fumarate 300 mg daily, continued for at least 12 months after the last dose).

Formulations. 100 mg and 500 mg intravenous vials; dilute to 1 to 4 mg/mL in 0.9 percent sodium chloride; do not give as a bolus. Subcutaneous formulations exist for malignancy only. Store at 2 to 8 degrees Celsius.

Baseline. Hepatitis B surface antigen and core antibody, hepatitis C and HIV serology, tuberculosis screen, full blood count, immunoglobulins (IgG, IgA, IgM), CD19 count, pregnancy test, and vaccination update at least 4 weeks before the first dose (pneumococcal, influenza, hepatitis B; no live vaccines).

Monitoring. Observe during and for at least 1 hour after the first infusion. Full blood count at 4 weeks and every 3 months. IgG before each course and every 6 months. CD19 count before repeat dosing where used. Late neutropenia can appear weeks to months after dosing.

Infusion reaction management. Slow or stop the infusion for fever, rigors or hypotension; give antihistamine, hydrocortisone and paracetamol and restart at half the rate once resolved; for anaphylaxis give intramuscular adrenaline 0.5 mg (adult).

Stop or hold thresholds. Hepatitis B reactivation, progressive multifocal leukoencephalopathy symptoms, severe infection, severe mucocutaneous reaction, IgG under 3 g/L with recurrent infection (consider immunoglobulin replacement), or neutrophils under 1.0 x 10^9/L.

Referral and escalation. Specialist initiated. Refer for infection, persistent hypogammaglobulinaemia, or neutropenia.