What is happening re the location of the proposed UK Rituximab trial that people are fundraising for at the moment is really a question for Professor Edwards - I heard from Jonathan last week but I don't know if he is around at the moment….
These are my notes on the two relevant presentations that went into the MEA report on the Invest conference this year:
Dr Geraldine (Jo) Cambridge – Principle Research Fellow Inflammation, Division of Medicine Faculty of Medical Sciences, University College London (UCL) – and Fane Mensah
B cell biology and Rituximab treatment in patients with ME/CFS
Photos:
https://www.google.co.uk/search?q=dr+jo+cambridge+ucl&biw=1608&bih=1018&source=lnms&tbm=isch&sa=X&ved=0ahUKEwio2PfvpJ3NAhUqDMAKHfaQBOoQ_AUICCgD#imgrc=gak1pFTSAUHgnM%3A
https://www.google.co.uk/search?q=fane+mensah&biw=1608&bih=1018&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjS5vCepZ3NAhWJKcAKHSCGBvYQ_AUIBygC#imgrc=-_UG0Q1aW7KqzM%3A
Dr Jo Cambridge gave an excellent and easy to understand presentation on B cell function in general, how B cell dysfunction and the production of autoantibodies might relate to the immunopathology of ME/CFS, and the practical aspects of using rituximab to treat non-malignant conditions.
Dr Cambridge started off by explaining how she belonged to a group of researchers at UCL, including Professor Jonathan Edwards, who have a particular interest in how a drug called rituximab, which was originally used to treat a malignant condition called lymphoma, depletes the population of a specific type of immune cells called B cells. Rituximab was then found to effectively treat some cases of rheumatoid arthritis (RA) and other autoimmune conditions such as SLE/lupus where inflammation is an important part of the underlying disease process.
Photo rituximab:
http://www.meassociation.org.uk/wp-content/uploads/9-18-2010-rituximab.gif
Among the key points made in relation to the use of rituximab in RA and to the way in which it might also act in ME/CFS:
· This research has produced information about how rituximab can produce a significant remission of symptoms (in around 70% of RA patients) and the resumption of symptoms (in around 60% of RA patients) once the B cell population has been restored.
· Patients with high levels of autoantibodies (= antibodies that attack the body’s own tissues) have a far more pronounced and predictable response than those with no evidence of autoantibodies.
· B cells are killed off very quickly by rituximab – the drug binds to cells that express what is called a CD-20 receptor. This usually occurs within a week of the infusions - which are given intravenously over 6 hours. The B cells therefore start to disappear from the blood within days and from other tissues at varying rates. But the dynamics of the clinical response – which takes from 1 to 5 months after depletion of the B cells – suggests that it is the constantly generated B-cell product (possibly an autoantibody) and not the B cells themselves that need to be reduced for remission to occur.
· A considerable proportion of the B cells are not depleted and remain in protective sites in lymphoid and inflamed tissues.
· Levels of autoantibodies can therefore remain raised, even in the presence of an improvement in clinical symptoms.
· These observations suggest that only a proportion of parent B cells and autoantibodies are actually ‘pathogenic’ (= involved in disease causing mechanisms). And, as a proportion of patients then relapse, the autoimmune response underlying the disease causing process must be self-sustaining.
· Patients are not therefore normally ‘cured’ by rituximab and symptoms can worsen when the B cells start regenerating – which takes place 6 to 9 months after the infusion. However, some patients have a more extended period of remission after the B cells return.
· Side-effects are rare and although reductions in serum antibody levels (which provide protection against infections) occur, the effects on protective immunity are mild and serious infections are not a problem.
In relation to the use of rituximab in ME/CFS, we are very much at the beginning of a learning process – which follows on from the clinical trials that have been carried out and published by Drs Fluge and Mella in Norway.
The UCL research team is concentrating on investigating B cell biology in order to try and identify differences between people with ME/CFS and healthy controls to see if this can help identify people with ME/CFS who are more likely to respond to this drug.
The group has hypothesized that rituximab may be reducing fatigue levels in ME/CFS as a result of decreasing the production of immune system chemicals called cytokines (i.e interferon alpha) through the removal of autoantibody containing (pro-inflammatory) immune complexes. Rituximab would therefore be working by stopping the production of (as yet) only tentatively identified pathogenic antibodies.
Fane Manesh, a PhD student at UCL, then spoke about the work that has been carried out into phenotyping sub-populations of naïve and memory B cells in people with ME/CFS. The group has published data on these B cells, showing that a specific cell maturation marker called CD-24 is upregulated or retained by the newly generated B cells. As a result, they have been using cells from patients and healthy controls to follow B cell development patterns, and interactions with T cells, in response to certain stimuli. The group has also established an
in vitro system (= performed in a test tube) where they can compare the metabolic function of B cells in ME/CFS patients and in healthy controls as well as what is termed mitochondrial mass.
Dr Cambridge did not put any 'meat on the bone' regarding which clinicians might/would be involved in a UK trial; where the trial might/would take place; the development of the protocol; and when a clinical trial might/would take place here in the UK till the Q and A session – where she explained the difficulties involved in setting up a UK trial for a drug like rituximab.
According to Dr Cambridge, it is going to be very hard to get a clinical trial going here in the UK due to a combination of developing a protocol, obtaining ethical approval, finding committed clinicians to carry out the work, the work being expensive in both cost and time, and the lack of pharmaceutical backing for a drug that is quite expensive to use – something that has occurred in other clinical trials involving rituximab.
Dr Cambridge also repeated the advice that has come from Drs Fluge and Mella in Norway that rituximab should not be used on patients with ME/CFS outside proper clinical trials in our present state of knowledge.
CS note: I was going to ask Dr Cambridge over lunch what she thought about the less positive patient evidence from people with ME/CFS who have been treated with rituximab in America outside the Norwegian clinical trial (an important point that was raised during the clinical and research meeting in Sussex with Dr Amolak Bansal and myself three weeks ago) but wasn't able to do so.
Further information:
Mensah F et al. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Clinical Experimental Immunology. 2016,184 :237-47.
Most recent MEA statement on rituximab:
http://www.meassociation.org.uk/2016/05/rituximab-update-by-the-me-association-23-may-2016/
