Rituximab Associated Hypogammaglobulinaemia

Rituximab associated hypogammaglobulinaemia is a fall in serum IgG, IgA and IgM after treatment with anti-CD20 antibody. It develops over months, may persist for years, and raises the risk of serious infection.

Pathophysiology. Rituximab removes CD20-positive B cells, including precursors of plasma cells. Long lived plasma cells that lack CD20 spare existing IgG, but when B cell reconstitution is delayed, antibody levels fall.

It is reported in about 10 to 40% of treated patients depending on the disease and the definition, with persistent low IgG in a smaller share. Risk rises with repeated courses and higher cumulative dose, low IgG before treatment, older age, and combined use of cyclophosphamide, mycophenolate or high dose corticosteroids.

Late onset neutropenia and hepatitis B reactivation are related complications.

• Recurrent sinopulmonary infection, pneumonia and bronchiectasis
• Herpes zoster, urinary infection and skin infection
• Severe infection, including sepsis and opportunistic infection, with combined immunosuppression
• Late onset neutropenia (4 weeks to 6 months after treatment) with fever and mouth ulcers
• Reactivation of hepatitis B: fatigue, jaundice, raised transaminases
• Poor vaccine responses for at least 6 months after the last dose
• Often no symptoms and found on routine testing

• Serum IgG, IgA and IgM before each course and at 3 months, 6 months and then 6-monthly for at least 12 months after the last dose.
• B cell count (CD19 or CD20 positive): absent for 6 to 12 months and then recovering; persistent depletion beyond 12 months predicts prolonged low IgG.
• Specific antibody titres (tetanus, pneumococcal) when replacement is considered.
• Full blood count and differential at 4 weeks and 3 months for neutropenia.
• Hepatitis B and C serology and HIV test (HBsAg, anti-HBc) before treatment, and HBV DNA if positive.
• Exclusion of other causes: myeloma, protein loss, and concurrent drugs.
• Chest imaging for recurrent infection.

Differential diagnosis.

• Primary antibody deficiency unmasked by treatment (common variable immunodeficiency)
• Hypogammaglobulinaemia from the underlying disease (lymphoproliferative disease, nephrotic syndrome)
• Hypogammaglobulinaemia from other drugs (corticosteroids, mycophenolate, BTK inhibitors)
• Protein losing states
• Laboratory artefact

• Before rituximab: check IgG, IgA, IgM, B cell count, hepatitis B and C serology, HIV, and vaccination status. Give inactivated vaccines (influenza, pneumococcal conjugate, COVID-19) at least 2 to 4 weeks before the first dose if the disease allows. Avoid live vaccines.
• Hepatitis B: for HBsAg-positive patients or anti-HBc-positive patients, start entecavir 0.5 mg orally once daily on an empty stomach (reduce frequency at creatinine clearance under 50 mL/min) before rituximab and continue for at least 12 months after the last dose. Monitor HBV DNA and ALT every 3 months.
• Immunoglobulin replacement for IgG under 4 g/L with recurrent or severe infection: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L. Use a time limited course of 6 to 12 months, then stop for 3 to 6 months to judge recovery.
• Antibiotic prophylaxis for recurrent infection: azithromycin 500 mg orally three times weekly or 250 mg once daily in adults, after ECG shows QTc under 450 ms.
• Pneumocystis prophylaxis with combined immunosuppression or high dose corticosteroids (prednisolone 20 mg or more daily for 4 weeks or more): co-trimoxazole 960 mg orally three times weekly, for at least 6 months after the last dose.
• Late onset neutropenia: filgrastim 1 to 5 microgram/kg subcutaneously daily until neutrophils recover to over 1.0 x 109/L. Fever with neutropenia is an emergency: after blood cultures give piperacillin with tazobactam 4.5 g intravenously every 6 hours in adults (adjust to renal function).
• Dose reduction: use the lowest effective rituximab dose and the longest tolerable interval, and avoid routine repeat dosing when the disease is in remission.
• Re-vaccination 6 months or more after the last dose, when B cells begin to recover.

Special groups.

• Children: hypogammaglobulinaemia can be prolonged, so monitor B cells and IgG closely and avoid live vaccines until recovery.
• Patients with granulomatosis with polyangiitis, lupus or multiple sclerosis on maintenance rituximab: track IgG before every dose.

Monitoring. IgG, IgA, IgM and B cell count at 3 months, 6 months and then every 6 months for at least 12 months after the last dose. Full blood count at 4 weeks and 3 months after each course. HBV DNA and ALT every 3 months if on antiviral prophylaxis. Trough IgG every 3 to 6 months on replacement.

Referral and escalation. Refer to immunology for IgG under 4 g/L with infections, persistent B cell depletion beyond 12 months, or a failure of vaccine response. Urgent for sepsis, neutropenic fever, or hepatitis flare.