|Trade names||Rituxan, MabThera, others|
|intravenous infusion only (never bolus or "push")|
|Biological half-life||30 to 400 hours (varies by dose and length of treatment)|
|Excretion||Uncertain: may undergo phagocytosis and catabolism in RES|
|Chemical and physical data|
|Molar mass||143859.7 g/mol|
|(what is this?)|
Rituximab, sold under the brand name Rituxan among others, is a medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, idiopathic thrombocytopenic purpura, pemphigus vulgaris and myasthenia gravis. It is given by slow injection into a vein.
Common side effects, which often occur within two hours of the medication being given, include rash, itchiness, low blood pressure, and shortness of breath. Other severe side effects include reactivation of hepatitis B in those previously infected, progressive multifocal leukoencephalopathy, and toxic epidermal necrolysis. It is unclear if use during pregnancy is safe for the baby. Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. When it binds to this protein it triggers cell death.
Rituximab was approved for medical use in 1997. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale price in the developing world as of 2014 is US$148–496 per 100 mg. In the United Kingdom this amount costs the NHS approximately £182. The average wholesale price in the United States of a typical treatment for rheumatoid arthritis (1,000 mg IV dose, 2 weeks apart) would be $14,100 a month in 2014.
Rituximab destroys both normal and malignant B cells that have CD20 on their surfaces and is therefore used to treat diseases which are characterized by having too many B cells, overactive B cells, or dysfunctional B cells.
Rituximab has been shown to be an effective rheumatoid arthritis treatment in three randomised controlled trials and is now licensed for use in refractory rheumatoid disease. In the United States, it has been FDA-approved for use in combination with methotrexate (MTX) for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more anti-TNF-alpha therapy. In Europe, the license is slightly more restrictive: it is licensed for use in combination with MTX in patients with severe active RA who have had an inadequate response to one or more anti-TNF therapy.
There is some evidence for efficacy, but not necessarily safety, in a range of other autoimmune diseases, and rituximab is widely used off-label to treat difficult cases of multiple sclerosis, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy and autoimmune anemias. The most dangerous, although among the most rare, side effect is progressive multifocal leukoencephalopathy (PML) infection, which is usually fatal; however only a very small number of cases have been recorded occurring in autoimmune diseases.
Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis (for example granulomatosis with polyangiitis, formerly Wegener's), bullous skin disorders (for example pemphigus, pemphigoid—with very encouraging results of approximately 85% rapid recovery in pemphigus, according to a 2006 study), type 1 diabetes mellitus, Sjogren's syndrome, anti-NMDA receptor encephalitis and Devic's disease, Graves' ophthalmopathy, autoimmune pancreatitis, Opsoclonus myoclonus syndrome (OMS), and IgG4-related disease. There is some evidence that it is ineffective in treating IgA-mediated autoimmune diseases.
Rituximab is being used off-label in the management of kidney transplant recipients. This drug may have some utility in transplants involving incompatible blood groups. It is also used as induction therapy in highly sensitized patients going for kidney transplantation. The use of rituximab has not been proven to be efficacious in this setting and like all depleting agents, carries with it the risk of infection.
- Severe infusion reaction.
- Cardiac arrest
- Cytokine release syndrome
- Tumor lysis syndrome, causing acute renal failure
- Immune toxicity, with depletion of B cells in 70% to 80% of lymphoma patients
- Pulmonary toxicity
- Bowel obstruction and perforation
Two patients with systemic lupus erythematosus died of progressive multifocal leukoencephalopathy (PML) after being treated with rituximab. PML is caused by activation of JC virus, a common virus in the brain which is usually latent. Reactivation of the JC virus usually results in death or severe brain damage.
Rituximab has been reported as a possible cofactor in a chronic Hepatitis E infection in a person with lymphoma. Hepatitis E infection is normally an acute infection, suggesting the drug in combination with lymphoma may have weakened the body's immune response to the virus.
Mechanisms of action
The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.
Rituximab tends to stick to one side of B cells, where CD20 is, forming a cap and drawing proteins over to that side. The presence of the cap changed the effectiveness of natural killer (NK) cells in destroying these B cells. When an NK cell latched onto the cap, it had an 80% success rate at killing the cell. In contrast, when the B cell lacked this asymmetric protein cluster, it was killed only 40% of the time.
The following effects have been found:
- The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
- Rituximab has a general regulatory effect on the cell cycle.
- It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
- It elicits shedding of CD23.
- It downregulates the B cell receptor.
- It induces apoptosis of CD20+ cells.
The combined effect results in the elimination of B cells (including the cancerous ones) from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.
Based on its safety and effectiveness in clinical trials, rituximab was approved by the U.S. Food and Drug Administration in 1997 to treat B-cell non-Hodgkin lymphomas resistant to other chemotherapy regimens. Rituximab, in combination with CHOP chemotherapy, is superior to CHOP alone in the treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas. In 2010 it was approved by the European Commission for maintenance treatment after initial treatment of follicular lymphoma.
Rituximab is currently co-marketed by Biogen Idec and Genentech in the U.S., by Hoffmann–La Roche in Canada and the European Union, Chugai Pharmaceuticals, Zenyaku Kogyo in Japan and AryoGen in Iran.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.
In 2014 Genentech reclassified rituxan as a specialty drug, a class of drugs that are only available through specialty distributors in the US. Because wholesalers discounts and rebates no longer apply, hospitals would pay more.
Patents on the drug in expired in Europe in February 2013 and in the US in September 2016. By February 2017 several biosimilars had been approved in India and one biosimilar had received approval in Europe.
Chronic fatigue syndrome
A potential use for rituximab was identified by two Norwegian doctors who were treating people who had cancer with rituximab; two people also had chronic fatigue syndrome and the CFS improved. As of 2017 this use had been explored in some small clinical trials and was undergoing some larger ones; it was unclear as of 2017 whether there is enough benefit in light of the known adverse effects, for rituximab to be a viable treatment for CFS.
Other anti-CD20 monoclonals
The efficacy and success of Rituximab has led to some other anti-CD20 monoclonal antibodies being developed:
- ocrelizumab, humanized (90%-95% human) B cell-depleting agent.
- ofatumumab (HuMax-CD20) a fully human B cell-depleting agent.
- Third-generation anti-CD20s such as obinutuzumab have a glycoengineered Fc fragment (Fc) with enhanced binding to Fc gamma receptors, which increase ADCC (antibody-dependent cellular cytotoxicity). This strategy for enhancing a monoclonal antibody's ability to induce ADCC takes advantage of the fact that the displayed Fc glycan controls the antibody's affinity for Fc receptors.
- Drugs.com International brand names for rituximab Archived 2016-04-22 at the Wayback Machine. Page accessed April 1, 2016
- "Rituximab". The American Society of Health-System Pharmacists. Archived from the original on 27 March 2016. Retrieved 8 December 2016.
- Tandan, Rup; Hehir, Michael K.; Waheed, Waqar; Howard, Diantha B. (August 2017). "Rituximab treatment of myasthenia gravis: A systematic review". Muscle & Nerve. 56 (2): 185–196. doi:10.1002/mus.25597. ISSN 1097-4598. PMID 28164324. Archived from the original on 2017-11-05.
- Bosch, Xavier; Ramos-Casals, Manuel; Khamashta, Munther A. (2013). Drugs Targeting B-Cells in Autoimmune Diseases. Springer Science & Business Media. pp. 1–4. ISBN 9783034807067. Archived from the original on 2017-11-05.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- "Rituximab". International Drug Price Indicator Guide. Retrieved 28 November 2015.
- British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 638. ISBN 9780857111562.
- "Drugs for Rheumatoid Arthritis". The Medical Letter. 56 (1458): 127-32. 22 December 2014. (Subscription required (. ))
- Saini KS, Azim HA Jr, Cocorocchio E, Vanazzi A, Saini ML, Raviele PR, Pruneri G, Peccatori FA (2011). "Rituximab in Hodgkin lymphoma: Is the target always a hit?". Cancer Treat Rev. 37 (5): 385–90. doi:10.1016/j.ctrv.2010.11.005. PMID 21183282.
- Edwards J, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close D, Stevens R, Shaw T (2004). "Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis". N Engl J Med. 350 (25): 2572–81. doi:10.1056/NEJMoa032534. PMID 15201414.
- Tak PP, Kalden JR (2011). "Advances in rheumatology: new targeted therapeutics". Arthritis Research & Therapy. 13 (Suppl 1): S5. doi:10.1186/1478-6354-13-S1-S5. PMC . PMID 21624184.
- McGinley, MP; Moss, BP; Cohen, JA (January 2017). "Safety of monoclonal antibodies for the treatment of multiple sclerosis". Expert opinion on drug safety. 16 (1): 89–100. doi:10.1080/14740338.2017.1250881. PMID 27756172.
- Paul, Marla (May 20, 2009). "Popular Cancer Drug Linked to Often Fatal 'Brain Eating' Virus". Northwestern University News and Information. Archived from the original on May 29, 2010. Retrieved 2009-05-22.
- "Press Announcements". Fda.gov. Archived from the original on 2009-05-13. Retrieved 2013-04-29.
- Froissart A, Veyradier A, Hié M, Benhamou Y, Coppo P (August 2015). "Rituximab in autoimmune thrombotic thrombocytopenic purpura: A success story". Eur J Intern Med. 26: 659–65. doi:10.1016/j.ejim.2015.07.021. PMID 26293834.
- Braendstrup P, Bjerrum OW, Nielsen OJ, et al. (April 2005). "Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura". Am. J. Hematol. 78 (4): 275–80. doi:10.1002/ajh.20276. PMID 15795920.
- Patel V, Mihatov N, Cooper N, Stasi R, Cunningham-Rundles S, Bussel JB (2007). "Long-term responses seen with rituximab in patients with ITP" (PDF). Community Oncology. 4 (2): 107. doi:10.1016/s1548-5315(11)70061-4. Archived (PDF) from the original on 2007-09-29.
- Shanafelt TD, Madueme HL, Wold RC, Tefferi A (2003). "Rituximab for Immune Cytopenia in Adults: Idiopathic Thrombocytopenic Purpura, Autoimmune Hemolytic Anemia, and Evans Syndrome" (PDF). Mayo Clinic Proc. 78: 1340–1346. doi:10.4065/78.11.1340. PMID 14601692. [permanent dead link]
- A. Razzaque Ahmed, M.D.; Zachary Spigelman, M.D.; Lisa A. Cavacini, Ph.D.; Marshall R. Posner, M.D. (October 26, 2006). "Treatment of Pemphigus Vulgaris with Rituximab and Intravenous Immune Globulin". N Engl J Med. 355: 1772–1779. doi:10.1056/nejmoa062930. PMID 17065638.
- Jacob A, Weinshenker BG, Violich I, McLinskey N, Krupp L, Fox RJ, Wingerchuk DM, Boggild M, Constantinescu CS, Miller A, De Angelis T, Matiello M, Cree BA (2008). "Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients". Arch Neurol. 65 (11): 1443–1448. doi:10.1001/archneur.65.11.noc80069. PMID 18779415. Archived from the original on 2009-03-04.
- "Rituximab Treatment of Patients with Severe, Corticosteroid-Resistant Thyroid-Associated Ophthalmopathy". Archived from the original on 2017-08-22. Retrieved 2011-10-19.
- "Immunomodulators and Rituximab in the Management of Autoimmune Pancreatitis". Archived from the original on 2014-05-02. Retrieved 2014-04-30.
- Pranzatelli, Michael R.; Tate, Elizabeth D.; Travelstead, Anna L.; Longee, Darryl (2005-01-01). "Immunologic and Clinical Responses to Rituximab in a Child With Opsoclonus-Myoclonus Syndrome". Pediatrics. 115 (1): e115–e119. doi:10.1542/peds.2004-0845. ISSN 0031-4005. PMID 15601813. Archived from the original on 2015-12-22.
- Arezou Khosroshahi; Z. S. Wallace; J. L. Crowe; T. Akamizu; A. Azumi; M. N. Carruthers; S. T. Chari; E. Della-Torre; L. Frulloni; H. Goto; P. A. Hart; T. Kamisawa; S. Kawa; M. Kawano; M. H. Kim; Y. Kodama; K. Kubota; M. M. Lerch; M. Löhr; Y. Masaki; S. Matsui; T. Mimori; S. Nakamura; T. Nakazawa; H. Ohara; K. Okazaki; J.H. Ryu; T. Saeki; N. Schleinitz; A. Shimatsu; T. Shimosegawa; H. Takahashi; M. Takahira; A. Tanaka; M. Topazian; H. Umehara; G. J. Webster; T. E. Witzig; M. Yamamoto; W. Zhang; T. Chiba; John H. Stone (July 2015). "International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease". Arthritis & Rheumatology. 67 (7): 1688–1699. doi:10.1002/art.39132. PMID 25809420. Archived from the original on 2015-05-11.
- He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, Grando SA, Zone JJ, Maverakis E (2015). "Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab". JAMA Dermatol. 151 (6): 646–50. doi:10.1001/jamadermatol.2015.59. PMID 25901938.
- "Genentech: Products - Product Information - Immunology - Rituxan RA Full Prescribing Information". Archived from the original on 2007-12-13. Retrieved 2007-12-03.
- Burton C, Kaczmarski R, Jan-Mohamed R (2003). "Interstitial pneumonitis related to rituximab therapy". N Engl J Med. 348 (26): 2690–1; discussion 2690–1. doi:10.1056/NEJM200306263482619. PMID 12826649.
- "Reports of Bowel Obstruction and Perforation with RITUXAN (rituximab)" (PDF). Roche Canada. 2006-11-10. Archived (PDF) from the original on 2014-03-27.
- "Rituximab (marketed as Rituxan) Information". Archived from the original on 15 November 2009. Retrieved 15 November 2009.
- "Rituximab, RA and PML" (PDF). Archived (PDF) from the original on 2008-09-16. Retrieved 2008-09-14.
- "Chronic Hepatitis After Hepatitis E Virus Infection in a Patient With Non-Hodgkin Lymphoma Taking Rituximab" (PDF). Retrieved 2008-09-14.
- Seyfizadeh, Narges; Seyfizadeh, Nayer; Hasenkamp, J; Huerta-Yepez, S (2016). "A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections". Crit Rev Oncol Hematol. 97: 275–290. doi:10.1016/j.critrevonc.2015.09.001. PMID 26443686.
- "Scientists discover why a specific cancer drug is so effective". KurzweilAI. doi:10.1182/blood-2013-02-482570. Archived from the original on 2013-05-03. Retrieved 2013-04-29.
- Rudnicka, D; Oszmiana, A; Finch, DK; Strickland, I; Schofield, DJ; Lowe, DC; Sleeman, MA; Davis, DM (Jun 6, 2013). "Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity". Blood. 121 (23): 4694–702. doi:10.1182/blood-2013-02-482570. PMID 23613524.
- T Shaw, J Quan, and M Totoritis, "B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience", Ann Rheum Dis. 2003 November; 62(Suppl 2): ii55–ii59.
- Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M. (2006). "The epitope recognized by rituximab". Blood. 108 (6): 1975–1978. doi:10.1182/blood-2006-04-014639. PMID 16705086.
- "Why San Diego Has Biotech", Fikes, Bradley J. San Diego Metropolitan, April 1999. Accessed June 20, 2008.
- DrugBank DB00073 Archived 2014-01-05 at the Wayback Machine.
- Maloney DG, Grillo-López AJ, White CA, et al. (September 1997). "IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma". Blood. 90 (6): 2188–95. PMID 9310469.
- Scott SD (1998). "Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin's lymphoma". Cancer Pract. 6 (3): 195–7. doi:10.1046/j.1523-5394.1998.006003195.x. PMID 9652253.
- Harrison's Principles of Internal Medicine, Longo et al. McGraw Hill Medical 2011 page 931
- "Roche Gets EC Nod for Follicular Lymphoma Maintenance Therapy". October 29, 2010. Archived from the original on October 31, 2010.
- "www.who.int" (PDF). Archived (PDF) from the original on 2015-05-13.
- Saporito, Bill (27 October 2014). "Hospitals Furious at Cancer-Drug Price Hikes". Time. Archived from the original on 20 October 2015. Retrieved 26 October 2015.
- "Archived copy". Archived from the original on 2016-06-07. Retrieved 2016-06-09.
- "Biosimilars of Rituximab". Generics and Biosimilars Initiative. 14 April 2017. Archived from the original on 2017-03-31. Retrieved 2017-04-29.
- Castro-Marrero, J; Sáez-Francàs, N; Santillo, D; Alegre, J (March 2017). "Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome". British journal of pharmacology. 174 (5): 345–369. doi:10.1111/bph.13702. PMC . PMID 28052319.
- "Genmab.com / HuMax-CD20 (ofatumumab)". Archived from the original on 2007-09-11. Retrieved 2007-12-03.
- "Fc-structure". Archived from the original on 2007-11-10. Retrieved 2007-12-03.
- Eccles, SA (2001). "Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?". Breast cancer research : BCR. 3 (2): 86–90. doi:10.1186/bcr276. PMC . PMID 11250751.
- Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun. 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMC . PMID 25578468.