Rituximab Study Update: Researchers Focus on Rare Gene Variant

[Cort]

Update from Haukeland University regarding the Rituximab and other studies

The Rituximab Study

For those who don't remember (such as myself - another blog I wrote that I promptly forgot) here's the study:

• [fright]
  
  [/fright]The first two infusions (500 mg/m2, max 1000 mg, or placebo) are given two weeks apart followed by maintenance infusions 500 mg fixed dose (or placebo), at 3, 6, 9 and 12 months. The study will be double-blinded and placebo-controlled. (No one will know what is getting what)....
• The follow-up will be for 24 months, and the code for intervention will be revealed after the last included patient has been to 24 months visit and the database is locked.
• The study also includes endothelial cell (blood vessel), exercise and gastrointestinal functioning substudies.

The recent Update stated:

• Enrollment - often the most difficult part of the study - finished up 8 months ago
• Almost all the patients have received their treatments
• They will break the code in Sept of next year - 16 months from now
• Expect a paper publication in 2018
• They, with other research groups, will be pounding the patients blood samples with tests (auto-antibodies, immune signatures, cell metabolism and genetics) in an attempt to figure out what's going on in those who respond and those who don't.
• They have created an extensive biobank which includes samples from all time points and from former studies.

For more about the study read here.

The Genetic Study

[fleft]

[/fleft]Haukeland is also focusing on the genetic predisposition to ME/CFS. You may have heard of families where ME/CFS, fibromyalgia or similar diseases predominate. These families provide another possible entry point - possibly the quickest and easiest entry point of all - into understanding ME/CFS.

This is because the genetic weak points in genetically predisposed families could point an arrow at issues in other people. An genetically derived immune abnormality in one family could translate into the same abnormality that was produced in another way in another person with ME/CFS. The genetic abnormalities found in afflicted families also provides fertile pathways for more research.

The Haukeland research group has completed exon sequencing of 18 people from two families with multi-generational cases of ME/CFS and are beginning on a third family. (Exome sequencing is a form of gene sequencing often used to pick genetic variations associated with diseases.)

The group believes they have found several variants in the first two families including one found in two out of every 1000 people in Europe. Finding a rare gene variant in the population at large that pops up regularly in ME/CFS families would be the equivalent of hitting a grand slam. Instead of having to work with multiple genes that work together to increase the risk of ME/CFS researchers could focus on one. That would be an unexpected gift.

It's no surprise, therefore, that the Haukeland group is focusing on this variant. The group is interested enough in this genetic anomaly to insert it into cells and begin testing them in order to determine it's impact. Thus far, the gene appears to be doing what they expected it to do, and they believe it may help us understand what is happening in ME/CFS.

Fluge and Mella aren't the only ones examining families with ME/CFS. Dr. Bateman of the Bateman-Horne Center and Dr. Isabel Barao of the Simmaron Research Institute are also studying families with multi-generational cases of ME/CFS. If those studies come up with similar genetic variants watch out!

Final thoughts

How gratifying and really how lucky we are to have these two cancer researcher devote themselves so wholeheartedly to this disease. They had no background at all in ME/CFS prior to discovering that chemotherapy helped some of their ME/CFS patients with cancer get better.

Now, though, Fluge and Mella are not just doing a large study; they've basically created a research and treatment center -a COE really, that is examining ME/CFS from multiple angles and involves outside researchers. They've packed substudies into their Rituximab trial, they're looking at genetics, the UK is involved in looking closely at B-cells, they've created a biobank, they're producing hypothesis papers, and they've also examined other treatment possibilities. They're have basically immersed themselves in ME/CFS.

Two Norwegian cancer experts! Who would have ever thought? It just shows that help is out there in places you would never expect...

Update, RituxME study

Multi-center study RituxME completed enrollment of all 152 participants in September 2015. By the summer holidays, all patients in Bergen, Trondheim, Notodden and Oslo have completed their course of treatment, and study center in Tromsø provides final treatment in September.

As known RituxME a double blind study, meaning that neither the patient or treating know about the individual patient is receiving active medication or placebo. Blinding is maintained until the last participant has finished one year of follow-up after stopping treatment, and we will therefore be able to break the code in September 2017. The results of RituxME study will be published in a scientific paper during 2018.

Research biobank at Haukeland University Hospital has been expanded with blood tests before treatment from all participants, and together with samples from previous studies and the ongoing cyclofosfamidstudien, these blood samples a unique material for research on disease mechanisms and a possible biomarker.

There is currently a lot of activity in the laboratory at Haukeland, and it is partnered with several national and international institutions on study on including autoantibodies, immune signatures, cell metabolism and genetics, where material from the biobank included. We continue to take samples to the Biobank at fixed times their studies until the last patient has completed follow-up.

Kari Sørland
Programme coordinator

 

[Who Me?]

So until then I'll just kick back and take nurofen.

 

[Gijs]

I still wonder how rituximab interact with NK-cel dysfunction. It doesn't make sense. Somebody an idea?

 

[Tony L]

@Gijs Are you thinking that functional NK cells are essential for rituximab to kill B-cells?

Rituximab can kill by several pathways So I assume these would be used in patients with compromised NK function.

Does that help?

 

[Who Me?]

Wouldn't they first have to find out what subsets this works on? As far as I know people with active infections should not get this. So where does low nk function fit into that?

No way would I try this until there are a lot of questions answered.

 

[Cort]

A couple of years ago I asked Dr. Kogelnik if he was an ME/CFS patient what would he try - Valcyte, Valtrex or Rituximab - and he said Rituximab. He said they were seeing some patients with great outcomes; obviously not all of them but some.

It's obviously going to be a subset...If its a small subset then I wonder if these patients could have some other undiagnosed disease. I also, wonder, though AKA Rachel's story, if these kind of miraculous I went from being bed bound to being back at work stories happen with Rituximab in other diseases? I wonder if that kind of thing is unique to ME/CFS.

 

[EYAKLLE]

they may have some other undiagnosed disease yes.
i worry that giving rituximab to some true ME patients may spoil their outcome later on arv s and prevent an arv response, if appropriate for them

 

[Cort]

I just updated the original post quite a bit and added a section on their genetic study. Plus it struck me how lucky we are:

How gratifying and really how lucky we are to have these two cancer researcher devote themselves so wholeheartedly to this disease. They had no background at all in ME/CFS prior to discovering that chemotherapy helped some of their ME/CFS patients with cancer get better.

Now, though, Fluge and Mella are not just doing a large study; they've basically created a research and treatment center that is examining ME/CFS from multiple angles and involves outside researchers. It's an extraordinary thing.

 

[tatt]

can I remind you of the UK study trying to work out how to identify groups that might benefit from rituximab http://onlinelibrary.wiley.com/doi/10.1111/cei.12749/abstract

 

[Cort]

can I remind you of the UK study trying to work out how to identify groups that might benefit from rituximab http://onlinelibrary.wiley.com/doi/10.1111/cei.12749/abstract

You certainly have a point. I know of a prominent doctor who's quite concerned about Rituximab and viruses. We'll certainly learn a lot from this study since it's big enough I would think - 150 patients - to include a variety of patients. It's interesting, though, that we haven't heard or at least I haven't heard of any really negative side effects. I'm a bit surprised by that but I missed them.

 

[Who Me?]

they may have some other undiagnosed disease yes.
i worry that giving rituximab to some true ME patients may spoil their outcome later on arv s and prevent an arv response, if appropriate for them

I don't get why you call it 'true" ME. Why not just say misdiagnosed?

 

[Who Me?]

You certainly have a point. I know of a prominent doctor who's quite concerned about Rituximab and viruses. We'll certainly learn a lot from this study since it's big enough I would think - 150 patients - to include a variety of patients. It's interesting, though, that we haven't heard or at least I haven't heard of any really negative side effects. I'm a bit surprised by that but I missed them.

I think they aren't talking about the negative side effects because 1. maybe they can't, and 2. it would look bad. There is a guy who has GWS, I can't think of his name but he says rtx almost killed him. And then there is Whitney Dafoe.

I remember someone on the staff at PR making a big deal out of patients talking about how they feel. In fact I think @Remy has a post here about it.

 

[Remy]

I think they aren't talking about the negative side effects because 1. maybe they can't, and 2. it would look bad. There is a guy who has GWS, I can't think of his name but he says rtx almost killed him. And then there is Whitney Dafoe.

I remember someone on the staff at PR making a big deal out of patients talking about how they feel. In fact I think @Remy has a post here about it.

Oh, it was something about patients in studies not saying anything that might influence the researchers prior to the study completion. Like all the researchers are so busy reading and being influenced by patient forums that are supposed to be by and for the, um, patients.

 

[Who Me?]

Oh Right @Remy. They'd be pretty stupid researchers if they let anecdotal stories influence data.

I have heard that there is someone on PR who talks like she is doing great but when she really isn't. I think @bobby knows the guy with the gws that got really sick.

 

[Remy]

It's been interesting to me that I ran across rituximab a lot when I was researching the tyrosine kinase inhibitor, imatinib (Gleevec).

I don't want to be that person that sees only one theory in everything...but it's kind of coincidental, is it not, that rituximab also has the ability to relieve severe mastocytosis? Is this the subset?

Induction Of Remission Of Frequent Idiopathic Anaphylaxis With Rituximab
Saturday, March 1, 2014
Exhibit Hall B (Convention Center)
Arturo Borzutzky, MD, Pamela S. Morales, MD, Veronica Mezzano, MD, Sofia Nussbaum, A. Wesley Burks, MD FAAAAI

Rationale: Frequent idiopathic anaphylaxis (IA) is a severe allergic disease of unknown etiology, with no standardized safe and effective treatment.
Methods: Case report.
Results: We report an 18-year-old girl with asthma and allergic rhinitis who developed mild chronic urticaria and frequent episodes of anaphylaxis characterized by sudden-onset pruritus, erythema, hives, abdominal pain, diarrhea, stridor and wheezing. Anaphylaxis occured every 3-30 days during 16 months, presenting spontaneously or after eating, with no specific triggers. Several episodes were witnessed and confirmed by experienced allergists. All episodes were promptly relieved by intramuscular epinephrine. Several food challenges to suspicious foods or additives were negative. Laboratory studies showed elevated total IgE of 334 UI/ml. Systemic mastocytosis was ruled out with normal baseline serum total and free tryptase, negative D816V c-Kit mutation, and normal histopathology of skin nevi, bone marrow and stomach. Ga68-PET/CT and intraplatelet serotonin ruled out carcinoid. The patient failed to respond to H1 and H2 blockers, montelukast, ketotifen, high-dose systemic corticosteroids, mycophenolate mofetil, omalizumab and elimination diets. The patient ceased to have anaphylaxis and urticaria 10 days after two doses of rituximab 1000 mg every 14 days. After 6 months, B cell count normalized and the patient restarted chronic urticaria symptoms and IA every 3-7 days. Retreatment with two doses of rituximab 500 mg every 14 days led again to full remission of anaphylaxis with follow-up of 4 months after retreatment.
Conclusions: This is the first report of successful treatment of IA with rituximab. This case suggests B-cell depletion as a novel highly effective treatment for IA.

 

[Who Me?]

@Remy new puppy pic! Is that the same dose as in the study? Or is it a smaller dose? That would be interesting to see if subclinical dose of rtx does anything.

 

[Who Me?]

This is a quote from professor Edwards re: Rituximab. As you may know he is on the board at PR and is constantly saying it is the best thing for us. Then why is he saying it won't work? And this is not the first time he's did it.

This is why I'm not sitting around waiting for it.

So far we do not have clear evidence for rituximab being useful in ME/CFS so the problem is a way off I think.

Here is the link to the thread

http://forums.phoenixrising.me/inde...reatment-contraindications.42213/#post-682930

 

[Cort]

It's been interesting to me that I run across rituximab a lot when I was researching the tyrosine kinase inhibitor, imatinib (Gleevec).

I don't want to be that person that sees only one theory in everything...but it's kind of coincidental, is it not, that rituximab also has the ability to relieve severe mastocytosis? Is this the subset?

Who knew? That's really interesting...At some point things from all different directions are going to come together.

 

[Justin]

I have been doing more research and I am wondering if ME is some linked to Autoimmune Encephalopathy or ADEM. Both this illness respond to immunotherapy and both present clinically like both illness when they are not in there most severe forms.

 

[bobby]

I think @bobby knows the guy with the gws that got really sick.

I vaguely remember a story but I have no idea who that is... I'll let it simmer for a while in my brain, who knows, maybe I'll remember!