Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes.
BACKGROUND
Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature.


METHODS
We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out.


RESULTS
We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia.


CONCLUSIONS
With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany melina.makatsori08@imperial.ac.uk.
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Makatsori
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Kiani-Alikhan
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Manson
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Verma
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Leandro
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Gurugama
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Longhurst
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Grigoriadou
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Buckland
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Kanfer
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Hanson
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Ibrahim
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Grimbacher
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Chee
From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
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Seneviratne
D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects* / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000150:complications / Q000188:drug therapy*; D004406:Dysgammaglobulinemia / Q000139:chemically induced*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D016393:Lymphoma, B-Cell / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab
D058846:Antibodies, Monoclonal, Murine-Derived; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D000069283:Rituximab