Rituximab (Rituxan) =================== * D.T. Selewski * G.V. Shah * R.J. Mody * P.A. Rajdev * S.K. Mukherji ## Abstract **SUMMARY:** Rituximab is a monoclonal antibody that was first approved by the FDA as an antineoplastic agent designed to treat B-cell malignancies. This article will review the mechanism of action and clinical role of this anti-B-cell agent. ## Abbreviations FDA : US Food and Drug Administration FSE : fast spin-echo Rituximab is a monoclonal antibody that targets CD20, a specific B-cell surface antigen. Rituximab (Rituxan; Biogen-IDEC/Genentech, South San Francisco, California) was the first monoclonal antibody approved for the treatment of non-Hodgkin lymphoma.1 In 1997, the FDA approved rituximab for the treatment of refractory low-grade lymphoma.2 This medication has since been used for the treatment of a number of CD20-positive B-cell malignancies.3,4 The selectivity of the drug for B-cells led to further investigations involving autoimmune B-cell−driven diseases, including rheumatoid arthritis.5 Rituximab has since been approved for the treatment of rheumatoid arthritis by the FDA. ## Mechanism of Action Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, which is a B-cell differentiation marker.6 CD20 is a cell-surface marker specifically found on pre-B and mature B lymphocytes and is not found on other cell types or free in circulation.7 The only binding site for rituximab is CD20 on B-cells. The binding of rituximab to cell surface CD20 located on the B lymphocytes results in destruction of the lymphocyte by 3 potential mechanisms, including complement-dependent cytotoxicity, stimulation of apoptosis, or antibody-dependent cytotoxicity (Fig 1.) Complement-mediated cytotoxicity most likely is the dominant mechanism in vivo.8 ![Fig 1.](http://www.ajnr.org/https://www.highwirestage.com/content/ajnr/31/7/1178/F1.medium.gif) [Fig 1.](http://www.ajnr.org/content/31/7/1178/F1) Fig 1. Schematic illustration of the mechanism of action of rituximab. The antibody labels B lymphocytes, which have the CD20 cell marker. These cells are then killed by 1 of 3 mechanisms: antibody-dependent cytotoxicity, complement-dependent cytotoxicity, or stimulation of apoptosis. Illustration by Priya A. Rajdev. ## Clinical Indications Rituximab has been approved by the FDA for various B-cell non-Hodgkin lymphomas (clinical case: Figs 2 and 3) and rheumatoid arthritis. There are multiple off-label uses, including chronic lymphocytic leukemia, systemic lupus erythematosus, multiple sclerosis, autoimmune hemolytic anemia, posttransplant lymphoproliferative disorder, graft-versus-host disease, pemphigus vulgaris, chronic immune-mediated thrombocytopenia, and Evans Syndrome. ![Fig 2.](http://www.ajnr.org/https://www.highwirestage.com/content/ajnr/31/7/1178/F2.medium.gif) [Fig 2.](http://www.ajnr.org/content/31/7/1178/F2) Fig 2. A 68-year-old woman presented with clumsiness, dropping things from her right hand, difficulty speaking, and right facial droop. *A*, T2-weighted axial FSE image of the brain shows patchy areas of increased T2-signal-intensity edema surrounding a low T2-signal-intensity lesion at the left temporal and frontal parietal lobes. *B*, T1-weighted postcontrast axial spin-echo image of the brain shows irregular and patchy enhancement of the lesion. Surrounding edema is seen as a low T1 signal intensity. A biopsy of the mass was performed, and CD20-positive B-cell lymphoma was diagnosed. ![Fig 3.](http://www.ajnr.org/https://www.highwirestage.com/content/ajnr/31/7/1178/F3.medium.gif) [Fig 3.](http://www.ajnr.org/content/31/7/1178/F3) Fig 3. The patient was admitted and received chemotherapy with methotrexate, vincristine, and rituximab. Follow-up MR imaging was performed 2 cycles into her chemotherapy. *A*, T2-weighted axial FSE image shows only residual edema as high T2 signal intensity in the deep white matter of the left frontal parietal lobes. *B*, Enhanced T1-weighted axial spin-echo image shows resolution of the enhancing mass. ## Administration Rituximab is a prescription drug administered intravenously. The half-life is relative to the dose and number of doses administered but ranges between 1.6 and 20 days.9 The medication remains detectable in the serum for ≤6 months after a single infusion. B lymphocyte depletion typically occurs by 2 weeks and recovery begins at 6 months and continues until 12 months.10,11 Patients may continue to have subtle abnormalities in B lymphocyte populations for several years following treatment. ## Side Effects There are several specific US boxed warnings on the package insert12: #### Transfusion Reaction. Severe transfusion reactions resulting in anaphylaxis characterized by fever, hypotension, bronchospasm, urticaria, and angiodema. Eighty percent of cases seen with the first infusion. #### Progressive Multifocal Leukoencephalopathy. Progressive multifocal leukoencephalopathy is a serious central nervous system infection due to the JC virus, which typically occurs within 12 months of the first infusion. Diagnosis requires MR imaging and spinal tap.13 #### Skin. Severe mucocutaneous reactions resembling Stevens-Johnson reactions or toxic epidermal necrolysis. #### Tumor Lysis Syndrome. Tumor lysis syndrome is caused by tumor cell death typified by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. It may be complicated by acute renal failure. #### Infections. Patients are susceptible to opportunistic infections, including pneumocystis pneumonia.14 Patients are also prone to severe viral infections with parvovirus B19, varicella, cytomegalovirus, or herpes simplex virus.15 #### Hepatitis. Reactivation of hepatitis B has been reported, resulting in fulminant hepatitis and hepatic failure. Screen high-risk patients before the initiation of therapy. ## Economic Issues Rituximab costs approximately $630 for a 10-mg vial. Typical dosing regimens range from 375 to 500 mg/m2 for 1–4 doses, depending on the indication but can be as high as 1000 mg for rheumatoid arthritis. ## Clinical Issues Patients require periodic laboratory follow-up with complete blood count, comprehensive metabolic panel, immunoglobulin levels, and lymphocyte counts/subpopulations. 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Blood 2002;99:1486–88 [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czo5OiI5OS80LzE0ODYiO3M6NDoiYXRvbSI7czoyMDoiL2FqbnIvMzEvNy8xMTc4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) * Received March 10, 2010. * Accepted after revision March 12, 2010. * Copyright © American Society of Neuroradiology