Jonathan Edwards : Rituximab

[Jonathan Edwards]

That's interesting - I didn't know that drug doses were calculated by initial testing. I had thought doses were calculated in relation to weight only. So the Rituximab dose formula isn't based on testing of Rituximab itself?

Nobody knows what the right dose of rituximab is. The original dose recommendation of 375mg/metre squared x 4 doses was based on just how much drug they had in the fridge when they did the pilot study. Over a period of twenty years various bits of evidence have suggested that the dose we use for autoimmunity is roughly right but it is not well established. The current trend for giving two doses for induction is really just based on how much drug you can reasonably give in a day. The spacing apart of two weeks is an artefact of my pilot trial with cyclophosphamide that people have stuck with because they do not know where it comes from.

BUT, the one thing I would say is that Drs Fluge and Mella are developing the longer term treatment schedule in an extremely intelligent and imaginative way. They are watching exactly what is happening as they go along and adjusting accordingly. It might be possible to get away with a much smaller initial dose but I suspect their follow up doses are pretty much right.

 

[Jonathan Edwards]

Rituximab was approved for use in RA in about 2007. The rationale for its use in autoimmunity is indeed still not well understood by many physicians. But when there are hundreds of practitioners using a drug and regularly meeting and exchanging experience practical issues tend to get sorted out. The problem for ME is that physicians who might treat it may not have this experience.

 

[Jonathan Edwards]

As far as I am aware, nobody is suggesting that rituximab is a one-off cure for ME/CFS. I believe it will have to be a lifetime treatment, as after rituximab depletes the B cells that are driving autoimmunity, I understand that these cells will slowly reestablish themselves after some time. So it needs another rituximab dose to deplete them again.

Perhaps @Jonathan Edwards can confirm this.


It's interesting that in this post Prof Edwards mentions that for many patients, taking a tenth of the normal dose of rituximab may be just as effective as the full dose, in terms of creating complete B cell depletion.

This offers potential to save quite a bit of money in the long term, if you only use a 10th of the rituximab dose. I wonder if there might be lower risks of side effects with lower doses as well.

You probably wouldn't do this on your first doses, the doses where you test to see if rituximab is efficacious for you; but having established efficacy, there may be the scope for lower doses.

Yes, regular repeats of rituximab are the norm, although in some cases it may be as far apart as three to four years. Judging precisely when to repeat treatment is the most important part of the protocol and one which I suspect many physicians may not understand unless they are involved in the background science.

 

[Jonathan Edwards]

I just have a question regarding the dosage of Rituximab, and was hoping @Jonathan Edwards could answer me.

At Kolibri, the Norwegian clinic that treats ME-patients with Rituximab, the two first doses are at 1 g each with follow up doses at 500 mg. At the Haukeland trials my understanding is that the dosage was determined individually for height and weight. So I was wondering if the differences in dosage, with Kolibri`s being higher, could affect the outcome and the overall respons? I understand that it would certainly affect the amount of side effects and who has an increase in their ME-symptoms, which are far higher at Kolibri than at the trials. But could it also affect the response, could the amount of people responding somehow go down, the response disappear for some who would otherwise respond at a lower dosage, or the response get worse with this increase in dosage? I know this may be a dumb question, but in many other diseases it`s often a question of the right dose rather than the highest dose.

As far as we know there is no 'too much' rituximab dose. Side effects are not related to dose - they tend to occur early on with the start of the first infusion if at all. From other autoimmune diseases it looks as if the dose is not very critical - it is quite likely that we are giving more than many people need. On the other hand a half dose does not seem quite as good. I wouldn't get worried about dosage at all to be honest. The Kolibri dose is the one I devised for RA, for the sake of simplicity. The Haukeland dose may be a bit less for small people but will be about the same for heavy people.

 

[Jonathan Edwards]

Perhaps I should clarify the situation. Kati is basically right. I will try to sort out some of the further confusions. For anyone who is not aware I will just remind people that the autoimmune dose for rituximab was devised by me for very specific reasons to do with mechanisms of autoimmunity.

Firstly, there is no significant difference between standard oncological dose and autoimmune dose. The exact dosages may be calculated differently and the total amount may be divided into four rather than two infusions, but there is no material difference.

Secondly, there is no justification for using a low dose on the basis of 'prudence'. As has been pointed out I have previously noted that the standard dose may be more than a lot of people need to get full depletion for three months. However, to be of much use one needs to deplete for six months and both in routine RA care and in the Haukeland studies doctors have moved towards maintaining B cell depletion for much longer periods, which on balance makes sense, even if there are issues that need keeping an eye on. We also have some quite good evidence for even the standard dose not being as potent as we would really like and not giving full depletion for a small proportion of patients. So justification for reducing the dose would need to be based on a formal dose comparison study.

We have already heard Dr Beiger and Dr Mikovits talking about low doses of rituximab in a way that indicated clearly that neither of them knew what they were talking about. I strongly suspect that Dr De Meirleir has picked up on this. Giving small doses of rituximab is not 'prudent'. In order to break a cycle of autoantibody production even for a period of months you need complete depletion - both on theoretical grounds and based on experience in particular in lupus. Anything less than about 90% depletion tends to have no clinical benefit at all, as one would theoretically expect. The reasons are to do with complicated immunology. However, it is not too difficult to follow. If a self-controlling system has got into a vicious cycle then gentle actions are more likely to interfere with the remaining good functions of the system than hit the vicious cycle. If you blow gently at a snowball rolling down a hill you do not stop the snowball getting bigger, you just blow away the snow around it.

Moreover, the real dangers with rituximab are of post-infusion allergic reactions and pneumonitis and as far as we know these are UNRELATED to dose - they occur after the first infusion, even if small.

So giving small doses for 'prudence' is in my view stupid meddling. I also have reason to be angry about this.When I developed B cell depletion therapy for RA I thought it might do a lot of good but I realised that in the hands of stupid and irresponsible physicians it might do a lot of harm. We went through that with physicians in France and probably Belgium giving rituximab without monitoring adequately. The lesson was learnt but not without harm being done. I consider myself responsible at least in part for harm done by usage of the drug. As a result I am only too happy to act as an expert witness for the plaintiff in cases of negligence in relation to inappropriate use. The very last thing I, and also Oystein Fluge and Olav Meall, want to see in ME/CFS is usage by phsyciains who do not understand what they are doing. I sincerely hope that Dr De Meirleir is not playing around with it.

 

[BurnA]

This thread is a collection of Jonathan Edwards posts on Rituximab.
The idea is to provide an overview in one thread for people wishing to know more about Rituximab treatment.
It is a read only thread, if you have questions or comments on a particular post please refer back to the original thread where the post was copied from.

Thread is currently in progress 06 May 17, please check back when completed.