EBV in bone marrow of rheumatoid arthritis patients predicts response to Rituximab

[Marco]

This is very interesting in a number of respects. As I understand it :


A proportion of rheumatoid arthritis have a defective immune protection against EBV;

A proportion of RA patients have active EBV infection in B cells and bone marrow;

Treatment of RA patients with rituximab (RTX) leads to a greater improvement in symptoms in those with active EBV infection compared to EBV negative patients;

EBV may play a part in the etiology of RA either directly or through initiating an autoimmune response :

EpsteinBarr virus in bone marrow of rheumatoid arthritis patients predicts response to rituximab treatment

Conclusions. EBV and parvovirus genomes are frequently found in bone marrow of RA patients. The presence of EBV genome was associated with a better clinical response to RTX. Thus, presence of EBV genome may predict clinical response to RTX.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936947/?tool=pubmed

 

[alex3619]

Very interesting, ties in with what Lerner has been saying. Bye, Alex

 

[magnetronnie]

Thanks for posting this!
I've always wondered if EBV plays a role in the pathogenesis of CFS. Interesting article.

 

[heapsreal]

I think theres alot more to the herpes viruses then they realise. EBV was only discovered in the 1960s and not long after that they closed the book on it after finding it causes mono.
Thanks for posting.

cheers!!!

 

[Enid]

Very interesting - thanks Marco. Can't help noticing how often things come down to viruses (latent or otherwise) and immune coping problems.

 

[maryb]

Could be a big breakthrough if anyone takes the results seriously, haven't a lot of the top ME doctors said for years that the EBV virus gets into cells deep in the body, basically hiding away, so makes absolute sense that it is in the bone marrow too.

 

[heapsreal]

Also think this is why lerner keeps his patients on av's longer even though viral titres come down, which are only marker found in blood, not other tissues and marrow etc. Its all speculation at this stage until there is better testing but maybe lerner is onto something, i iwish someone would pick his brain more or teach another newby doc about it so his knowledge isnt lost and maybe improved on with time and improved technology. Even though viral markers in my blood have come down i feel there something missing, maybe missing these intracellular infections which maybe take more time, who knows??

 

[Tony Mach]

So they treated 35 patients. 15 had EBV, of which 12 were responders. 20 did not have EBV, of which 6 were responders.

If it is EBV, why did 6 out of 20 without EBV respond?

EBV is a Herpes-Virus, it is also called HHV-4. Why did they not test for other Herpes-Viruses? Like HHV-8 (which is latent in B-cells as well), HHV-6, CMV (HHV-5) and VZV (HHV-3)? Is the correlation better when considering most (or all) known human herpes viruses?

Furthermore, these are awfully small sample sizes. Does it hold up in larger sample sizes? My experience is, that with EBV (and herpes viruses) researchers get all excited because they find some spurious correlation in small samples sizes and when the correlation evaporates in larger studies, you don't hear much about it (like Montoya's work).

 

[Daffodil]

then why dont they just treat RA with valtrex? are they saying its molecular mimicry?

 

[snowathlete]

I posted on here just after the Ritoximab with a suggestion that Herpes viruses were in our bone marrow, i dont think i got any replies.

It makes sense because Ritoximab wipes out the B cells, but if Herpes is in the bone marrow, then when your body produces more, you relapse. This was my explaination for why some patients on the trial relapsed.

Personally i think it makes a lot of sense. On my post i also asked if anyone knew of any CFS/ME patients who had had bone marrow transplants (for whatever reason) and whether they got better. I think there is a chance that they would, especially if in conjuction with a treatment like Ritoximab. Bone marrow transplants are quite easy nowadays as i understand it.

 

[Daffodil]

i spoke to someone on the prohealth message boards years ago who had a bone marrow tx and it got rid of her CFS for a few years i think..then it came back.

i'm sure its a retrovirus and that is rarely eradicated with a bone marrow tx.

 

[snowathlete]

i spoke to someone on the prohealth message boards years ago who had a bone marrow tx and it got rid of her CFS for a few years i think..then it came back.

i'm sure its a retrovirus and that is rarely eradicated with a bone marrow tx.

Thanks so much for posting that Daffodil. I expect whatever the cause is needs to be removed from the body as fully as possible, perhaps a tx and a drug like Ritoximab might prove an effective treatment...

 

[Megan]

EBV is a Herpes-Virus, it is also called HHV-4. Why did they not test for other Herpes-Viruses? Like HHV-8 (which is latent in B-cells as well), HHV-6, CMV (HHV-5) and VZV (HHV-3)? Is the correlation better when considering most (or all) known human herpes viruses?

Good point. It would be interesting to know the status of other herpes viruses. But this study is very interesting given the context of the Norwegian study. It would be goog to know the EBV status (and other above viruses) of those that took part in the Norwegian group - I hope they are following up on this.

Also very interesting that they were picking up EBV in the bone marrow but not blood of so many people.

 

[anne_likes_red]

Interesting discussion.
Thanks for posting the study

I had a bone marrow biopsy as part of my original ME diagnosis-by-exclusion.
They said I had an abnormality; a "leukemia profile", but excluded cancer. They also excuded EBV in blood.
I had Mono years later, but I wonder if a related virus could have been responsible for the abnormal bone marrow profile.

I'm not even completely sure how a bone marrow transplant works but it seems an interesting option as a treatment, or partial treatment.

 

[alex3619]

Personally i think it makes a lot of sense. On my post i also asked if anyone knew of any CFS/ME patients who had had bone marrow transplants (for whatever reason) and whether they got better. I think there is a chance that they would, especially if in conjuction with a treatment like Ritoximab.

My best guess, and its only a guess as we know too little, is that a full treatment for some of us will require something like Rituximab and and a bone marrow transfusion together, or potentially other more powerful drugs that kill bone marrow cells first. This is not a safe procedure, some die. A similar procedure was noted a few years ago for MS, in which the patients fully recovered. However, a few died. Repeated courses of Rituximab might turn out to be safer than killing the bone marrow immune cells and rebuilding the immune system.

Bye
Alex

 

[Hope123]

Interesting article, Marco.

Some comments:

1) Initial Norwegian Rtx series -- all 3 patients started their CFS with EBV mono;

2) A number of patients in the trial (70%) had some sort of infection in the beginning but unclear how many with EBV mono (looks like less than 6)

3) One patient in series had autologous stem cell transplant -- i.e. she received her own blood after chemo/ radiation; she did not get an improvement with her CFS symptoms. Might have been different had she received an allogeneic transplant -- i.e. from another person.

4) I used to volunteer with kids in the hospital where bone marrow transplants were pioneered. It was and still is not a benign process as you have to undergo treatment to wipe out your own bone marrow, which leaves you open to all sorts of infections for several months. Probably much better than in the past but still not a piece of cake.

5) There are some ways of getting our own T-cells primed and better able to fight EBV by "training" them in a test tube and re-introducing them to our bodies. This type of treatment is being looked at for post-transplant lymphoproliferative disorder (PTLD) which is caused by EBV. I know at least Nancy Klimas is aware of this treatment. Seems less risky than bone marrow transplant but might need to be repeated?

Lots of questions, as usual.

 

[ixchelkali]

Very interesting, in light of the Norwegian Rituximab study. It might offer a clue as to the mechanism for the results they saw and/or an explanation of responders vs. non-responders. I hope they will check for various viral infections when they do the larger follow-up study, and see if they correlate to the results.

There are a couple of other papers on Epstein-Barr virus in rheumatoid arthritis patients that are reminiscent of ME/CFS as well:

Epstein-Barr virus and rheumatoid arthritis.

Epstein-Barr virus, arthritis, and the development of lymphoma in arthritis patients

 

[snowathlete]

i dont know how safe it is, but from what i read bone marrow transplants are quite easy compared to how they used to be. As i understand it they suck out some bone marrow from the doner, then transfuse it with the patients blood (presumably after having sucked out some of their bad bone marrow) and then it goes into the patients veins and the blood carries it to the bones itself.

im super interested in this, it could be a major component of treatment in the future.

 

[Tristen]

Wouldn't it be wild after 25 years to come full circle back to 1st base, and find EBV to be a key player in the pathology after all.

EBV hiding out in the B cells and bone marrow could very well make it undetectable by blood tests. I've only done the Labcorp "EBV, Chronic/Active Infection" test, and don't fully understand how to read it . My doc says my EBV is in remission, but I don't trust the accuracy of this test after these new developments. If anyone knows how to read this test, and my results, please jump in.

EBV Early Antigen Ab, IgG.......<2 Negative
EBV Ab VCA, IgG...................>8 Positive
EBV Nuclear Antigen Ab, IgG....>8 Positive


Just to throw a wrench in the whole Viral involvement in RA issue, Antibiotic Protocol (AP) therapy has become quite popular for RA Tx. Minocin is the most widely used and from what I am hearing, it's very effective. But I really don't know any of that stats on that. I know that Minocin has some anti-inflammatory effects, but it sounds as though it may be more than that. If it's hitting a bug, it's not a virus.

 

[snowathlete]

EBV hiding out in the B cells and bone marrow could very well make it undetectable by blood tests. I've only done the Labcorp "EBV, Chronic/Active Infection" test, and don't fully understand how to read it .

Sorry Tristen, i dont know how to interpret these, but i am close to getting the same tests done myself. Thing is, i am thinking the same thing as you - are the tests reliable? Well, they are reliable if the problem is in your blood i guess, but if they are intracelular or in the bone marrow, or hiden elsewhere then i guess the tests arent going to pick up on it.
That being the case, i am thinking about going straight to antivirals instead. Difficult.