Rituximab (trade names Rituxan, MabThera and Zytux) is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. Rituximab has been used as a treatment for auto-immune disorders such as reumatoid arthiritis and certain cancers. Norwegian researchers have tested the use of rituximab in patients with ME/CFS. Although the results initiatilly looked promising, a large randomized, double-Blind, placebo-controlled trial demonstrated that Rituximab is not associated with clinical improvement in patients with ME/CFS.
Medical uses[edit | edit source]
Rituximab is used to treat cancers of the white blood system such as leukemias and lymphomas, including non-Hodgkin's lymphoma and lymphocyte predominant subtype of Hodgkin's Lymphoma. Rituximab has been shown to be an effective rheumatoid arthritis and is now licensed for use in refractory rheumatoid disease. It is used off-label to treat multiple sclerosis and systemic lupus erythematosus.
Effectiveness in ME/CFS[edit | edit source]
Two Norwegian oncologists, Øystein Fluge & Olav Mella have investigated the use of Rituximab in patients with CFS extensively. In 2004 they became intrigued by a ME/CFS patient who developed Hodgkin's disease and improved significantly after chemotherapy with methotrexate. This was the first significant improvement in her ten years of being ill with ME/CFS and her ME/CFS symptoms reappeared after chemotherapy was stopped. Fluge & Mella suspected the involvement of B-cells and tried to replicate the effect of methotrexate, with rituximab. After a delay of 6 weeks – the time required to clear preexisting autoantibody-mediated inflammation – the patient’s symptoms improved markedly. In 2009 Fluge & Mella published a case series of 3 ME/CFS patients who're ME/CFS symptoms improved each time they’ve received a rituximab infusion.
This was followed by a small double-blind randomized, placebo-controlled trial in 2011. Although the trials primary end-point – self-reported fatigue scores 3 months after intervention – was negative, 10 out of 15 patients in the rituximab arm showed a clinically significant improvement later on in the trial, compared to only 2 in the Placebo-group. A subsequent Open-Label Phase II study on the correct dose and maintenance of rituximab in ME/CFS confirmed that approximately two-thirds of patients showed a clinically significant response. The results created a lot of media attention and excitement in the ME/CFS patient community. The fact that in some patients all ME/CFS symptoms improved suggested that rituximab might target a fundamental aspect of the illness pathology.
A larger, phase 3 study called RituxME was started with funding from the Norwegian ME Association, the Norwegian Research Council and other sources. 152 ME/CFS patients, selected using the Canadian diagnostic criteria, were randomized to receive either rituximab or a placebo. In 2017 Mella & Fluga announced the negative results of the RituxME early so that patients would not continue to try out the drug on their own. The results were finally published in the Annals of Internal Medicine in April 2019. Rituximab was not associated with clinical improvement in patients with ME/CFS.
Mode of action[edit | edit source]
Rituximab works in autoimmune disease by destroying memory B cells committed to producing autoantibodies that cause symptoms and signs of disease.The drug binds to the surface of the B cell by attaching to the CD20 molecule. This triggers cell death through several mechanisms including antibody dependent cytotoxicity and apoptosis. If the drug is infused slowly, B cells are removed without causing any unpleasant symptoms. Rituximab cannot target autoreactive cells specifically so it leads to depletion of memory B cells as a whole. This is probably not associated with major immunosuppression because antibodies to microbes are mostly made by long lived plasma cells derived in the past from memory B cells and these are not targeted by rituximab. Autoantibodies appear often to be produced by shorter lived plasma cells which die off rapidly.
B cell depletion with rituximab tends to last about 6 months. After that, when B cells return some patients will suffer an immediate relapse of autoimmune symptoms but others may continue well for a period of months or years and for some conditions apparently long term. So far it is unclear whether or not any effect in ME/CFS can continue long term or whether repeated treatment will be required, as is the case, for instance, for rheumatoid arthritis.
Risks & side effects[edit | edit source]
Rituximab is given by infusion in a hospital. Unwanted effects are not common but can be serious. Allergic reactions can normally be avoided by careful monitoring while giving the infusion very slowly at first. Sterile pneumonia-like episodes can occur within a few days after infusions. Susceptibility to infection may be increased if there are other reasons for being at risk but in general immunosuppression is not a major problem. 
Rarely, the temporary immunosuppression caused from Rituximab may cause a reactivation of a persistent enteroviral infection with potentially dangerous central nervous system complications. Another rare but usually fatal viral disease triggered in a weakened immune system during the use of Rituximab is Progressive Multifocal Leukoencephalopathy (PML), caused by the the human polyomavirus John Cunningham virus (JCV). PML is being researched by Dr. Eugene Major, a member of the NIH Post-Infectious ME/CFS Study. 
Rituximab was reportedly being offered to ME/CFS patients in the United States (Andreas Kogelnik at the Open Medicine Institute) and in Norway (a private clinic in Sandnes) but experts such as Jonathan Edwards has advised against this, stating in 2015 "As the person who established that rituximab is useful in autoimmune disease I would actually advise against this. Rituximab is very unlike most drugs in that you have to understand how to use it in considerable detail in order to give it safely and effectively". The British patient charity the ME Association has also advised against patients looking for treatment with the drug outside of clinical trials. In the RituxME trial, a higher percentage of serious adverse events with possible or probable relation to the intervention was noted in the rituximab group.
Evidence[edit | edit source]
- 2009, Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series (Øystein Fluge, Olav Mella)
- 2011, Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study (Øystein Fluge, Olav Mella, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H)
- 2013, Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls (Amolak Bansal, AS Bradley, B Ford)
- 2015, B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment (Øystein Fluge, Olav Mella, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O)
- 2016, Extended B cell phenotype in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A cross-sectional study(Full Text)
- 2016, Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome(Full Text)
- 2019, B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.
Ongoing studies[edit | edit source]
- The British patient charity, Invest in ME, supported a Rituximab study in the UK, led by Jonathan Edwards, but in February 2018, deemed "that a UK trial is not possible or advisable following the negative Norwegian trial results."Jonathan Edwards became interested in the use of Rituximab on ME/CFS patients after attending the Invest in ME International ME Conference in May 2013.
- The Norwegian team are running more trials:
- Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome (ME/CFS) (CycloME) (see Cyclophosphamide)
- B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study, (RituxME). Preliminary results are negative
- B-cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Very Severe Chronic Fatigue Syndrome
- RituxME - B-lymphocyte depletion using the anti-CD20 antibody rituximab (Mabthera®) in Myalgic Encephalopathy/Chronic Fatigue Syndrome ("RituxME")
- In late fall 2015, Dr. Francis Collins announced that the NIH was considering the possibility of sponsoring a clinical trial for Rituximab, as well as Ampligen and other treatments.
Talks and interviews[edit | edit source]
- Dr. Kenneth J. Friedman, discusses the drug Rituximab for those with ME/CFS (23 Jun 2014)
- Olav Mella speaks about the Rituximab study and ME/CFS future (12 May 2014)
- Chronic Fatigue Syndrome: Study Supports Autoimmune Disease Theory (ABC News, 24 October 2011)
- Immune system defect may cause ME (BBC News, 24 October 2011)
- Chronic fatigue syndrome eased by cancer drug (New Scientist, 19 October 2011)
Learn more[edit | edit source]
- Wikipedia - Rituximab
- IiME UK Rituximab Clinical Trial and B-Cell Research
- Health Rising Forum on Rituximab
- 2016, Fresh evidence points to a cause and possible treatments for chronic fatigue syndrome
- 2016, UK ME/CFS Rituximab Trial In Trouble? Is U.S. the Only Option?
- 2016, Lecture by Hanne Thürmer, Notodden. RituxME and current development (Hanne Thürmer)
- 2016, Rituximab - A Promising Treatment for ME/CFS
- 2016, Chronic Fatigue Syndrome: Rituximab Revisited (January 19)
- 2015, The Biggest Chronic Fatigue Syndrome Treatment Trial Begins: Fluge/Mella On Rituximab (20 January)
- 2015, B cell depletion benefits ME/CFS patients (Virology Blog, 9 July)
- 2015, Antibody wipeout found to relieve chronic fatigue syndrome (New Scientist, 1 July)
- 2015, Norwegian TV update - Rituximab treatment in Norway against ME
- 2013, Norwegian TV update on study
See also[edit | edit source]
References[edit | edit source]
- Mok, Chi Chiu (Dec 27, 2013). "Rituximab for the treatment of rheumatoid arthritis: an update". Drug Design, Development and Therapy. 8: 87–100. doi:10.2147/DDDT.S41645. ISSN 1177-8881. PMC . PMID 24403823.
- Fluge, Øystein; Bruland, Ove; Risa, Kristin; Storstein, Anette; Kristoffersen, Einar K.; Sapkota, Dipak; Næss, Halvor; Dahl, Olav; Nyland, Harald (2011). "Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study". PloS One. 6 (10): e26358. doi:10.1371/journal.pone.0026358. ISSN 1932-6203. PMC . PMID 22039471.
- Fluge, Øystein; Rekeland, Ingrid G.; Lien, Katarina; Thürmer, Hanne; Borchgrevink, PetterC.; Schäfer, Christoph; Sørland, Kari; Aßmus, Jörg; Ktoridou-Valen, Irini (Apr 2, 2019). "B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial". Annals of Internal Medicine. doi:10.7326/M18-1451. ISSN 1539-3704. PMID 30934066.
- Diamantopoulos, Panagiotis T.; Polonyfi, Katerina; Sofotasiou, Maria; Papadopoulou, Vasiliki; Kalala, Fani; Iliakis, Theodoros; Zervakis, Kostantinos; Tsilimidos, Gerassimos; Kouzis, Panagiotis; Kyrtsonis, Marie-Christine; Vassilakopoulos, Theodoros; Angelopoulou, Maria; Siakantaris, Marina; Vayopoulos, George; Kollia, Panagoula; Pangalis, Gerassimos; Viniou, Nora-Athina (December 2013), "Rituximab in the treatment of EBV-positive low grade B-cell lymphoma", Anticancer Research, 33 (12): 5693–5698, ISSN 1791-7530, PMID 24324119
- Rowe, Peter C. (Apr 2, 2019). "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Trial Fails to Confirm Earlier Observations of Rituximab's Effectiveness". Annals of Internal Medicine. doi:10.7326/M19-0643. ISSN 0003-4819.
- Fluge, Øystein; Mella, Olav (Jul 1, 2009). "Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series". BMC neurology. 9: 28. doi:10.1186/1471-2377-9-28. ISSN 1471-2377. PMC . PMID 19566965.
- Fluge, Øystein; Risa, Kristin; Lunde, Sigrid; Alme, Kine; Rekeland, Ingrid Gurvin; Sapkota, Dipak; Kristoffersen, Einar Kleboe; Sørland, Kari; Bruland, Ove (2015). "B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment". PloS One. 10 (7): e0129898. doi:10.1371/journal.pone.0129898. ISSN 1932-6203. PMC . PMID 26132314.
- "Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails". Simmaron Research. Nov 26, 2017. Retrieved Apr 28, 2019.
- Cancer Research UK - Rituximab (Mabthera)
- Major EO. (2010). Progressive Multifocal Leukoencephalopathy in Patients on Immunomodulatory Therapies. Annu Rev Med. 2010;61:35-47. doi: 10.1146/annurev.med.080708.082655.
- NRK television, Norway (Nov 27, 2015), A private clinic in Sandnes, Norway is treating ME with Rituximab (video)
- Phoenix Rising - Is there any way I can be treated with rituximab privately?
- Phoenix Rising - De Meirleir is using Rituximab?
- The ME Association - Rituximab – update by The ME Association | 23 May 2016
- Mensah, Fane; Bansal, Amolak; Berkovitz, Saul; Sharma, Arti; Reddy, Venkat; Leandro, Maria; Cambridge, Geraldine (2016), "Extended B cell phenotype in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A cross-sectional study", Clinical and Experimental Immunology, 184 (2): 237-247, doi:10.1111/cei.12749
- Loebel, M; Grabowski, P; Heidecke, H; Bauer, S; Hanitsch, LG; Wittke, K; Meisel, C; Reinke, P; Volk, H; Fluge, Ø; Mella, O; Scheibenbogen, C (2016), "Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome", Brain, behavior, and immunity, 52: 32-39, doi:10.1016/j.bbi.2015.09.013
- UK Rituximab Trial
- UK Rituximab Trial - Statements By Professor Jonathan Edwards and Invest in ME | July 2013
- ME Action - NIH Considering Ampligen and Rituximab Trials | 21 December 2015
double blinded trial - A clinical trial is double blinded if neither the participants nor the researchers know which treatment group they are allocated to until after the results are interpreted. This reduces bias. (Learn more: www.nottingham.ac.uk)
phase three - Last phase of clinical trials before a drug can be approved for public use. Whereas Phase one assesses basic safety, and Phase two assesses basic efficacy, Phase three uses many trial participants to fully assess both safety and efficacy, and overall benefit/risk.
apoptosis - a type of cell death in which a cell, in response to a threat, initiates a series of molecular steps that lead to its orderly death. This is one method the body uses to get rid of unneeded or abnormal cells. This form of cell suicide is also called programmed cell death.
adverse reaction - Any unintended or unwanted response to the treatment under investigation in a clinical trial.
enterovirus - A genus of RNA viruses which typically enter the body through the respiratory or gastrointestinal systems and sometimes spread to the central nervous system or other parts of the body, causing neurological, cardiac, and other damage. Since the first reports of myalgic encephalomyelitis (ME), enteroviruses have been suspected as a cause of ME. Enteroviruses have also been implicated as the cause of Type I diabetes, congestive heart failure, and other conditions. Enteroviruses include poliovirus, coxsackieviruses, and many others. New enteroviruses and new strains of existing enteroviruses are continuously being discovered. (Learn more: viralzone.expasy.org)
central nervous system (CNS) - One of the two parts of the human nervous system, the other part being the peripheral nervous system. The central nervous system consists of the brain and spinal cord, while the peripheral nervous system consists of nerves that travel from the central nervous system into the various organs and tissues of the body.
myalgic encephalomyelitis (ME) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.
chronic fatigue syndrome (CFS) - A fatigue-based illness. The term CFS was invented invented by the U.S. Centers for Disease Control as an replacement for myalgic encephalomyelitis (ME). Some view CFS as a neurological disease, others use the term for any unexplained long-term fatigue. Sometimes used as a the term as a synonym of myalgic encephalomyelitis, despite the different diagnostic criteria.
immunomodulator - a substance that affects the functioning of the immune system