lassesen 2:36 pm on May 15, 2016

Rituximab Review

I noticed today on facebook that someone posted a link to a NewScientist article Antibody wipeout found to relieve chronic fatigue syndrome (1 July 2015) dealing with the use of Rituximab. This is an anti-cancer drug. Since 2002, I have personally met physically several CFSers that went into full remission of CFS after treatment for cancer. The results are very believable that “Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years”.

I know that cancer treatment results in a massive change of the microbiome (exactly what my model asks for!). For example:

Chemotherapy-driven dysbiosis in the intestinal microbiome[2015]. “We found that faecal samples collected after chemotherapy exhibited significant decreases in abundances of Firmicutes (P = 0.0002) and Actinobacteria (P = 0.002) and significant increases in abundances of Proteobacteria (P = 0.0002) compared to samples collected before chemotherapy.”
Effect of chemotherapy on the microbiota and metabolome of human milk, a case report[2014]. “Chemotherapy caused a significant deviation from a healthy microbial and metabolomic profile, with depletion of genera Bifidobacterium, Eubacterium, Staphylococcus and Cloacibacterium in favor of Acinetobacter, Xanthomonadaceae and Stenotrophomonas.”
16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation[2014]. ” Chemotherapy was associated with a drastic drop in Faecalibacterium and accompanied by an increase of Escherichia.”
Oral microbiota distinguishes acute lymphoblastic leukemia pediatric hosts from healthy populations [2014]. “patients who developed subsequent bacteremia, or bloodstream infection exhibited decreased overall diversity and decreased abundance of taxa including Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella. Using machine-learning methods, we developed a BSI risk index capable of predicting BSI incidence with a sensitivity of 90 % at a specificity of 90 % based only on the pretreatment fecal microbiome.”
Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins [2013]. “Adolescent/young adult Hodgkin lymphoma survivors appear to have a deficit of rare gut microbes.”
Also, very intersting: Lymphoma caused by intestinal microbiota[2014]. “While there are not a plethora of studies demonstrating a connection between microbiota and lymphoma development, we believe that animal models are a system which can be exploited in the future to enhance our understanding of causation and improve prognosis and treatment of lymphoma.”

So, we have Staphylococcus decrease and Escherichia increase – which is precisely the type of shift that I have been advocating….

What does PubMed say for CFS?

There are just 12 studies at the moment, newspaper reports tend to often tilt results to sell newspaper.

“Recently, two clinical trials of B cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms.” [2016]
“In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses.” [2015]
“The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses.” [2011]

Bottom Line

We have a drug that causes remission in a subset of CFS patients [Fact]. The drug causes multiple effects: B-lymphocyte depletion and shift of the microbiome. Which effect (or a third unknown one) is the cause of remission?

IMHO the shift of the microbiome is more likely, many people have reported on this site (and by private email), significant improvement of symptoms by shifting the microbiome by just probiotics and supplements. There is no apparent link to B-lymphocyte with that treatment.

The model also predicts that any treatment will only be effective on subsets because the success is determined by the effectiveness of the treatment against the very specific strains that a person has. This is what is reported in the above literature — effective for a subset.

If you can get this prescribed by your MD, covered by insurance, and you fully understand the risks (see official literature), then give it a try. For myself, I would exhaust the appropriate probiotics and appropriate antibiotic paths first.

Troy 12:21 am on May 17, 2016

Have you considered that the dysbiosis might be a result of the active disease process and that correcting the disease process allows the microbiome to shift back to normal.

This seems to be Dr Naviaux’s theory.

http://www.sciencedirect.com/science/article/pii/S1567724913002390

He apparently has a CFS paper in the pipeline.
- lassesen 1:11 am on May 17, 2016
  
  Yes, but given many CFS patients have gone into remission within hours after a fecal transplant, I favor it as the most probable cause.
  
  Question is then, can you reverse the disease process in the same time frame?
  - Troy 1:18 am on May 17, 2016
    
    FMT remissions that last are extremely rare, presumably because something keeps pushing the microflora out of balance.
    
    And yes, the microbiome also rebalances in a mouse model of his hypothesis.
    
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334917/
    
    See microbiome in this table of corrected pathways:
    
    http://www.nature.com/tp/journal/v4/n6/fig_tab/tp201433t1.html
    - lassesen 2:10 am on May 18, 2016
      
      Thank you for the links. It will be interesting to see what comes out of that line of research which IMHO will likely be decades.
      
      This avenue does not appeal to me because it lacks the ability to predict probable items that will contribute to this. Second, my preference for models is the ability to explain existing observations, for example: Can it explain how Rituximab put people into remission (without vague waving of hands). This drug causing a shift in bacteria — especially an increase of undergrowth bacteria and a decrease of overgrowth bacteria families being reported by researchers who do not care about CFS, gives an explanation of how it works with the mechanism confirmed in independent studies.
      
      By my academic training, this makes it a good model. Whenever I read of a significant improvement by X, I investigate if it has impact on coagulation or the microbiome. If it does, does it have the right type of impact. This is called testing the model and is essential.
      - Troy 2:15 am on May 18, 2016
        
        Rituximab’s effect on the microbiome may be indirect. It may be correcting the microbiome through some kind of effect on Cell Danger Response.
        
        Rituximab is also entirely incapable of putting severe patients into remission. So far in these patients it’s either ineffective or dangerous.
hixxy 9:23 pm on June 2, 2016

Another study asserting that gut dysbiosis is a result of immune dysregulation rather than a cause:

“These data support a model of gut pathology in ME/CFS whereby dysregulated pDCs fail to promote the production of low-affinity IgA through the process of TI activation of B cells …”

http://www.jimmunol.org/content/196/1_Supplement/137.4
gse4joints 2:07 pm on August 4, 2016

The first chemotherapy was serendipitously the chlorine gas used as chemical warfare in WWI. Soldiers in the trenches who had leukemia and survived a gas attack showed improvement (i.e., reduced leukemic blood cell counts). This discovery spawned the type of harsh chemo drugs that attack/poison all cells but are meant to kill rapidly dividing cells such as in cancer, but also unfortunately kill others such as in the gut lining.

Then came not too long ago the narrowly targeted “biologic” drugs such as rituximab (RTX). They are very mild. Chemo drugs are like a cannon, biologics are like a scalpel. E.g., I would be very surprised if the incidence of diarrhea from RTX was anywhere near the incidence from harsh chemo agents.

So, I’d think it’s maybe not advisable to equate effects from mild anti-cancer biotherapy with those from harsh chemotherapy.

That said, depleting B-cells from circulation with RTX could conceivably reduce the amount of secretory IgA (which is the type of antibody secreted outside the body, into the gut, mouth etc) that is sent into the gut. But if a person’s secretory IgA is already not effective in controlling bad gut bacteria, then it wouldn’t seem that having less of it would matter much.