This is the first updated version of our information on the rituximab clinical trial that has been carried out in Norway.
What is rituximab and what is it normally used to treat?
Rituximab is a drug that is principally used to treat people with lymphoma (a cancer involving a specific type of white blood cell called lymphocytes). Rituximab has had American FDA approval since 1997 for this purpose. It can also be used to treat chronic lymphocytic leukaemia.
A lymphoma involves specialist immune system cells called B lymphocytes and the drug causes lysis (= disintegration) of the malignant B cells.
One of the main functions of B cells in a healthy body is to produce antibodies.
In scientific jargon rituximab is an anti-CD20 antibody – meaning that it acts against a protein called CD20, which is found on the surface of the B cells. Rituximab destroys both normal and cancerous B cells that have the CD20 protein present. It is therefore used in diseases where there are too many B cells, overactive B cells, or dysfunctional B cells.
Rituximab is also licensed for the treatment of severe active rheumatoid arthritis where other treatments have not been successful. In this case it acts by dampening down inflammation in the joints caused by immune chemicals called cytokines.
On an experimental unlicensed basis it has been used to treat a number of what are called autoimmune diseases – where the body produces harmful antibodies that attack normal tissues such as muscle and thyroid. These are known as autoantibodies. Examples of immune and autoimmune diseases where rituximab has been used include SLE (systemic lupus erythematosus), MS, Sjogren's syndrome and bullous skin diseases (eg pemphigoid).
The drug is co-marketed by Biogen Idec and Genentech in the US and by Hoffman La Roche in Canada and the European Union. It is sold under the trade names Rituxan and MabThera.
Are there any other drugs that act in a similar manner to Rituximab?
Yes, there are two other drugs that cause B cell depletion and have similar side-effects to rituximab. These are alemtuzumab/MabCampath (Genzyme) and ofatumumab/Arzerra (GlaxoSmithKline)
Why might rituximab be helpful in ME/CFS?
There is already plenty of sound research evidence to indicate that immune system dysfunction occurs in ME/CFS.
On current evidence it appears that this may involve low level activation of the immune system response, with production of immune chemicals called cytokines (which cause flu-like symptoms), rather than the type of immune system failure/deficiency that occurs in diseases such as HIV/AIDS.
Part of this activated immune response in ME/CFS may also involve the production of autoantibodies, and there is some research evidence to support this. However, it is premature to conclude that ME/CFS is an autoimmune disorder.
There is also some evidence that B cells may be involved in ME/CFS and this a site where reactivated viruses, such as HHV-6 and Epstein Barr, are present. But the delayed response to treatment in this clinical trial suggests that viral elimination is not the mode of action here.
So there are a number of sound theoretical reasons why this drug might be helpful in at least a sub-group of people with ME/CFS.
Where and why was this trial carried out?
The trial was carried out by oncologists (cancer experts) in Norway.
A few years ago they noticed that a person with ME/CFS who had developed a lymphoma, and was then treated with rituximab, made an unexpected and significant improvement lasting five months in their ME/CFS symptoms.
A small preliminary trial was carried out and the encouraging results on three patients were published.
Abstract available: www.ncbi.nlm.nih.gov/pubmed/19566965
The encouraging findings, coupled with a sound hypothesis as to why this drug might be helpful in ME/CFS, led to what is called a phase 2 clinical trial being carried out.
What happened in the trial?
This was a double-blind (meaning neither doctors nor patients knew which treatment was being used) placebo-controlled (meaning half of the group received rituximab and the other half received a placebo = saline) clinical trial.
30 patients were involved. They were assessed by a neurologist and all met the Fukuda CFS research definition. Most also met the Canadian definition.
Age range = 18 to 65. Mean age = 37.3 (80% female) in active treatment group. Mean age = 31.5 (60 % female) in the placebo group.
Mean disease duration = 5.1 years in the active treatment group; 8.1 years in the placebo group.
Preceding infection identified in 73% of the active treatment group and 67% in the placebo group.
23% of patients had a previous known autoimmune disease and 40% had a first-degree relative with an autoimmune disease.
Rituximab has to be given by infusion into a vein – it is not a drug that can be taken by mouth. Two infusions at a dose of 500mg per metre2 were given two weeks apart. The patients stayed overnight in hospital.
Both groups were followed up at regular intervals for a period of 12 months.
A range of self-reported and physician-assessed measures were recorded – including fatigue, mental functioning, overall health (SF-36) – to monitor progress and outcome in both groups.
XMRV status and lymphocyte subpopulations was also measured before treatment.
At baseline 3/30 patients had a B-cell count below the normal range. All those in the active treatment group were B-cell depleted at one month after intervention.
XMRV was not detected in any of the patients.
What are the results?
Although the numbers are small for a phase 2 clinical trial, the results are very encouraging.
10/15 people who received rituximab reported a moderate or major overall response.
2/15 people who received saline reported a moderate or major overall response
In most cases it took several months (2 to 7/12) after starting rituximab before an improvement in symptoms occurred with response durations of 2 – 15 months. Two patients have had major lasting responses, with no relapses, and are back at work.
The drug was well tolerated and no serious side-effects were reported. Two people noticed a worsening of their pre-existing psoriasis.
Is rituximab safe?
All drugs have side-effects and anti-cancer drugs often have a potential to cause serious side effects. So this is a drug that is only given in hospital by specialists who are used to working with it.
Infusion-related side-effects are quite commonly reported. Symptoms include low grade fevers and chills, nausea and vomiting, allergic reactions, tightness of the chest and throat, and lowered blood pressure.
A rare but much more serious side effect called a cytokine release syndrome (where immune chemicals are released) that can even be fatal. This is more likely to occur in patients with a lymphoma where lymphoma cells have entered the bloodstream.
Patients are therefore given an analgesic, an antihistamine and possibly a steroid before the infusion to reduce the possibility of side-effects.
Progressive multifocal leukoencephalopathy (PML), as a result of JC virus activation, has been reported in association with more prolonged use of rituximab.
Reactivation of hepatitis virus has also been reported – so this infection should be tested for before this drug is used..
Rituximab has to be used with caution in anyone with a history of heart or lung disease.
So this is a drug that has to be used and monitored in both the short term and long term with great care.
Have there been any criticisms of the trial?
Yes. A group of doctors wrote to the journal with a number of questions and criticisms relating to:
the theoretical basis and late response to treatment
blinding of the study
methodological concerns regarding measurement of fatigue
definition of improvement
patient and family links to autoimmune disease
the decision to proceed with an open-label follow up study
These criticisms were responded to in some detail by Professor Jonathan Edwards from University College London and the Norwegian researchers.
Correspondence relating to the trial results can be found here:
How much does this drug cost?
Rituximab is a fairly costly form of treatment. A 50 mL vial for infusion costs around £1000.
What happens next?
The research group in Norway are following up this work with a new open-label phase 2 trial that will investigate treatment with two infusions two weeks apart followed by maintenance infusions at 3, 6, 10 and 15 months.
There is also a need to carry out further trials involving other research groups to see if they reach similar conclusions regarding efficacy and safety.
Will my doctor be able to prescribe rituximab?
No. The whole process of drug discovery and clinical trial assessment is a long and costly process – especially when it involves a drug such as rituximab which has the potential to cause very serious short term and longer term side effects.
In simple terms the UK drug regulator – the Medicines and Healthcare Products Regulatory Authority (MHRA) – will want to see the results of phase 2 and phase 3 clinical trials, and then be sure that the drug is both effective and safe to use in ME/CFS, before it can be granted a product license.
Phase 2 trials test a treatment in patients to find out how well it works as well as its safety.
Phase 3 trials compare the treatment in much larger numbers, gather more information on how it works, and examine safety in more detail.
This a process that takes years rather than months.
Once this data is ready the MHRA in the UK, or the European Medicines Agency for the whole of the EU, can consider whether it can be given a product license for use in a specific condition.
What is the MEA doing?
The MEA is working very closely with the UK representatives of the Norwegian research group in order to obtain media publicity for the trial results. Examples so far include coverage via the BBC, New Scientist and Daily Mail.
BBC coverage: www.bbc.co.uk/news/health-15401746
Dr Charles Shepherd briefed the All Party Parliamentary Group on ME at Westminster, and the Forward ME Group at the House of Lords, on the results last week. The Chair of the APPG is writing to the Medical Research Council.
Dr Shepherd has discussed the results, and a possible preliminary protocol for a UK clinical trial, with leading experts in the use of this drug and with the chair of the MRC Expert Group on ME/CFS research.
The MEA has made it clear that the Ramsay Research Fund would be very happy to look at funding proposals for a UK clinical trial.
A note of caution: This is one small phase 2 clinical trial. We need to see the results from further clinical trials before coming to any conclusions about the way in which this drug might work in ME/CFS and whether or not it is an effective form of treatment for what may be a sub-group of people with ME/CFS who have an autoimmune component. We do not want to see a repeat of the false hopes created by the XMRV research.
Role of the MEA Ramsay Research Fund
Further research into the use of this drug clearly needs to be carried out and Dr Shepherd has already raised the issue of rituximab at a meeting at the Medicines and Health Products Regulatory Agency (who license new drugs for use in the UK) prior to publication of the paper.
The MEA Ramsay Research Fund would be very willing to consider helping to fund a UK clinical trial if anyone in a reputable clinical unit wants to apply.
Complete paper available online:
Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study
www.plosone.org/article/info:doi/10.1371/journal.pone.0026358
MEA information sheet prepared by Dr Charles Shepherd
We will be updating this information on a regular basis in response to comments and questions
2 November 2011 (version 2)
“XMRV was not detected in any of the patients”
All assay used were optimised to VP62 clone and not human gammaretroviruses. The host range of the viruses discovered in Lombardi et al. is unknown at this time, but the gag sequences are polytropic as are the gag sequences found in Lo et al.
“There is also some evidence that B cells may be involved in ME/CFS and this is a site where reactivated viruses, such as HHV-6 and Epstein Barr, are present. But the delayed response to treatment in this clinical trial suggests that viral elimination is not the mode of action here.”
MLV viruses do infect B cells. That relief for some patients from B cell depletion occurs when rituximab is given fits the HGRVs hypothesis of ME/cfs. This is the only hypothesis for ME/cfs, as it is testable.
The reason this does in fact support that a virus is being eliminated is because the pathology caused by the virus takes time to subside once virus eliminated.
Having been openly sceptical about XMRV for some considerable time, it suits Dr Shepherd not to point those facts out. Thanks for doing so JoT and hence presenting a more complete picture
JoT is right. This study might also show why Rituximab – depleted B cell therapy might improve ME patients.
“Development of XMRV producing B Cell lines from lymphomas from patients with Chronic Fatigue Syndrome
Francis Ruscetti1*, Vincent C Lombardi2, Michael Snyderman3, Dan Bertolette4, Kathryn S Jones1, Judy A Mikovits1”
If the B cells are a reservoir of HGRVs, then knocking out mature B cells would reduce retroviral load, but with their assays set to find the artificial clone VP62, Fluge and Bruland would not have detected any wild type HGRVs. Similar to the 0/0 studies that also used VP62 as their control.
If further research shows that this drug is indeed helpful for ME/CFS, how can it be administered to those people who also have severe multiple chemical sensitivity? Can the drug only be administered as described in these FAQs? Because if so, a lot of severely ill people will not be able to avail themselves of the potential benefits of the drug.
I am well aware that there is a small group of people with ME/CFS who still passionately believe that a retroviral infection is the cause of ME/CFS – despite the lack of sound scientific evidence to support this belief.
The fact is that those of us who have become increasingly sceptical and critical of the XMRV research have turned out to be correct.
The authors of the Rituximab paper state: “We have not been able to demonstrate XMRV or MLV infection in any of the 30 patients included in this study’.
So I think you are clutching at straws if you believe that Rituximab is acting by removing an as yet unidentified retroviral infection in the B cells.
Hello, I came to comment as, while I found your summary quite helpful, one point was confusing and needs to be confirmed. You wrote:
What happens next?
The research group in Norway are following up this work with a new open-label phase 2 trial that will investigate treatment with two infusions two weeks apart followed by maintenance infusions at 3, 6, 10 and 15 months.
But Dr Fluge in his response to vandermeer said “Based on the current study, there is now a Norwegian national initiative to do a randomized, blinded, multicenter Phase III study to verify or reject the conclusions of the PLoS One study. In the planning of this national study, results of our exploratory phase II study with Rituximab induction and maintenance will be important for the scheduling of the drug administration.” http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c&root=info%3Adoi%2F10.1371%2Fannotation%2F43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c
I’d appreciate it if you could make sure whether the Norwegian govt is funding Phase III trials as Fluge wrote, or Phase II as you wrote.
On coming to the site to comment & seeing your response to commenters, I would just like to say that perhaps you aren’t aware of how rude, and off-putting, your word choice is.
I won’t deconstruct the whole message, but just this sentence illustrates my point. You wrote,
“a small group of people with ME/CFS who still passionately believe that a retroviral infection is the cause of ME/CFS – despite the lack of sound scientific evidence to support this belief.”
First off – the group is not small that thinks that there is a possibility of a retroviral involvement in ME/CFS.
Not everyone who has an open mind subject “passionately” adheres to their understanding of the science – the use of the word is pejorative in this case.
You say “despite the lack of sound scientific evidence” – yet there is some, including what has been noted above, ALTER/Lo’s work. And John Hackett of Abbott Labs, when interviewed by Bloomberg at the AABB recently said “XMRV is a real virus, there’s no question,” http://www.bloomberg.com/news/2011-10-23/controversial-new-virus-tied-to-fatigue-not-transmitted-by-blood.html
and you use the word “belief” instead of hypothesis or possibility – again pejorative.
All I am saying is that there is no need to be so strongly offensive to those who hold a different understanding about the state of the science than you do – or in your words, passionately hold a different belief. You alienate people unnecessarily.
Why not work together and let the science speak for itself over time.
Re additional phase 2 and phase 3 study:
Sorry – but I do not know who is funding these studies. My reference to the open-label phase 2 trial comes straight from the paper. I do not have any further information on a phase 3 trial. I will try and find out and come back to you. Funding for the trial that has been published came from The Western Norway Regional Health Authority and a legacy.
Re passionate beliefs:
I think you are being a bit over-sensitive here. If you saw some of the very dogmatic (and sometimes quite rude) emails that I regularly receive on XMRV and retroviral infection you would understand why I sometimes use this terminology in relation to a small section of the patient community.
I think we will just have to agree to disagree about the lack of robust scientific evidence supporting a link between retroviral infection and ME/CFS!
I find it quite difficult to read even simplified accounts of research findings, but from what I’ve read it seems that the most exciting prospect here is not the use of Rituximab itself to treat ME, but the fact that it will almost certainly prove enormously helpful in the search for the cause of the illness, for the mechanism that perpetuates it, and hence for effective treatments.
I’d be interested in hearing what Dr Shepherd has to say about this: should we be excited by a drug that seems to have the potential to cause disastrous side-effects with long-term use, or should we put all our effort (and money) into learning what this drug tells us about our illness?
There is confirmed evidence published of a response to infection – in both adults and children from the group working in Dundee (Cardiovascular Epidemiology).
I would personally doubt XMRV itself, but I am not going to dismiss a retroviral infection as the cause, on the grounds of the muddle of XMRV itself.
I’m new to read medical data, and have a knack of asking stupid questions…but were the subjects given the steroid, antihistamine and analgesic in the trial? If yes, how do they know it was the Rituximab giving the relief?
As a side note, I think the strong response to anything for/against retrovirus is because until we know what it is, all we’re told is what it’s not. It’s a story we hear all the time. Until proper open minded research takes place and starts telling us what it is we’re allowed to theorise. The fact it’s taken so long for any genuine open minded funding to become available is disgraceful. I’ve known people who have been literally living in the dark for the last 20+ years with no help. Now I have this infliction I’m shocked that it could take so long, and still the government isn’t investing into an illness which affects such a lot of their population.