@Jonathan Edwards On the question of autoimmunity in ME, I'm puzzled by one thing. I simply don't understand why the success for rituximab would necessarily support an autoimmune hypothesis. As I understand it, one account of ME, especially post-infective ME, thats still be given serious consideration, is poor maintenance of herpesvirus latency in B cells (whether due to depleted EBV CD8+ or CB4+ T cells or whatever) So by this account, destroying B cells would presumably kill a large population of latently infected cells, so lead to temporary - and maybe longer - relief.
What am I missing?
In fact I have mentioned this on several threads but it is an issue of detailed evidence: subtle, but detail is crucial in understanding these things.
The reason why we think rituximab is working in autoimmune disease by an effect on antibody production rather than some knock on effect on other processes is the shape of the response curve. Improvement in RA, for instance, develops gradually over a period of 3-6 months. That can be tracked very accurately with C reactive protein levels going down and the fall is a long slow smooth curve. It takes much too long to be explained just by removal of early or midlife B cells. If you then track autoantibody levels - which my lab has been doing week in week out for fifteen years - you find the curve fits the improvement curve very well. It takes 3-6 months for the antibodies to decline because that depends on mature plasma cells dying off.
When rituximab was used in ME Dr Fluge and Dr Mella, who are oncologists, were no fully aware of the time course of improvement seen in autoimmune diseases. Their own disease, lymphoma, gets better very quickly because improvement is just due to the removal of the malignant b cells, which takes hours or at most a few days. So they were surprised to see that it took 3-6 months for the patients to improve until I was asked to comment on their paper and pointed out that the time course is exactly right for autoimmunity.
If rituximab was working by removing B cells full of EBV improvement should not take more than six weeks at the very most and I would expect it to be no more than three weeks. There is no reason why, if virus is removed today, that it should be producing symptoms in several weeks time. Usually when the body makes an effective immune response to EBV symptoms settle within a week or two. So the pattern of improvement with rituximab really makes no sense in terms of removing EBV.
What might be true is that EBV is necessary for a disordered autoimmune or autoinflammatory process to persist. So it might be that you will only get long term remission if you also clear away EBV. In fact this does not fit very well either since rituximab is very good at removing EBV and a lot of patients relapsed after improving - so again it does not seem to fit with continued presence of EBV being involved.