Rituximab

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. It is in trials for use as a potential treatment for some ME/CFS patients. It has been suggested patients who respond to Rituximab have an autoimmune disease. It is also in trials as a treatment for Multiple Sclerosis.

Medical uses
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, systemic lupus erythematosus and chronic fatigue syndrome.

Rituximab may be effective in completely eliminating Epstein-Barr virus infection from the peripheral blood.

Accidental ME/CFS treatment discovery
Two Norwegian oncologists, Øystein Fluge & Olav Mella, explain the history in their 2009 paper: "A patient with CFS had unexpected, marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin's disease. We reasoned that the transient CFS recovery was related to methotrexate treatment, which induces immunomodulation in part through B-cell depletion". This discovery led to them running a series of trials examining the efficacy of Rituximab for treating ME/CFS.

As of 2015 we had no formal proof that rituximab was effective for ME/CFS. The primary endpoint, at 3 months, of the randomised controlled trial published in 2011 was not met - there appeared to be no effect. However, at 6 months there did appear to be a significant benefit. In other autoimmune diseases rituximab can take many weeks to have effect and it is quite possible that in ME/CFS patients it has an effect that tends to take more than 3 months to show itself. So the 6 month endpoint is important. However, being a post-hoc analysis (i.e. in retrospect) the results do not provide formal statistical evidence for efficacy. A larger phase 3 trial is now in progress to establish formally whether or not the drug has a useful effect.

On Nov 21, 2017, Drs. Øystein Fluge and Olav Mella announced that their Rituximab trial had failed. They stated that they would focus their efforts on attempting to identify a subgroup of ME/CFS patients with an immune profile that would be responsive to Rituximab. The Drs. will publish a paper next year with the specifics of the failed trial.

Mode of action
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
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.

Private availability
Patients have stated that Rituximab is 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 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.

Evidence

 * 2015, Extended B-cell phenotype in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A cross-sectional study (Fane Mensah, Amolak Bansal, Saul Berkovitz, Arti Sharma, Venkat Reddy, Maria Leandro, Geraldine Cambridge)
 * 2015, Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome (Øystein Fluge, Olav Mella, Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Carmen Scheibenbogen)
 * 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)
 * 2013, Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls (Amolak Bansal, AS Bradley, B Ford)
 * 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)
 * 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)

Ongoing studies

 * 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 & interviews

 * 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

 * 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