Rituximab, Lupus and Chronic Fatigue Syndrome

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Some interesting possible intersections with ME/CFS, lupus and Rituximab. It's interesting that it took this long to test Rituximab in SLE.
  • Lupus is probably a syndrome with different immune subsets ("SLE is probably a syndrome with multiple different immune system abnormalities,")
  • Lupus may, at least for some patients, be a disease of reduced anti-inflammatory response (instead of an increased pro-inflammatory response). I think this seems more and more likely in ME/CFS and FM.
  • It appears that B-cells which produce interferon alpha are more prevalent in some lupus patients and B-cells that reduce inflammation are less prevalent.
  • High levels of IFN-a result in more autoantibody cell production. Killing off the B-cells with Rituximab reduces antibody production and the symptoms in lupus...
  • (Too many antibodies means a better chance of those antibodies attacking the body.)
  • The reduced anti-inflammatory response appears to be linked to polymorphisms in specific genes.
  • Other people with lupus appear to have a different immune mechanism...



TUESDAY, March 8, 2016 (HealthDay News) -- Scientists have found new clues that help explain what's going wrong in the immune systems of people with lupus -- insight they hope will lead to new therapies, or help guide current treatment choices.

Lupus has several forms, but the most common is systemic lupus erythematosus (SLE). In SLE, the immune system mistakenly produces antibodies against the body's own tissue. The onslaught can have widespread effects, damaging the skin, joints, heart, lungs, kidneys and brain, according to the Lupus Foundation of America.

The disease mostly strikes women, usually starting in their 20s or 30s, the foundation says.
In the new study, the researchers found evidence that in people with lupus, some of the immune system's "B cells" mature the wrong way -- so that they promote inflammation instead of fighting it.

The findings, published online March 8 in the journal Immunity, could help in developing new lupus therapies, said senior researcher Claudia Mauri. She is a professor of immunology at University College London in the United Kingdom.

In people without lupus, anti-inflammatory B cells appear to prevent excessive production of a protein called interferon-alpha, explained Mauri.

That's a critical job because too much interferon-alpha leads to too many B cells that produce antibodies, the study authors said. Antibodies are necessary soldiers in the body's defense against infection, but in lupus, some of those antibodies target the body itself.

"We will continue to work to develop new [treatment] strategies that harness the anti-inflammatory B cells in patients with SLE," Mauri said.

Right now, a number of drugs are used to treat lupus, including immune-system suppressors such as cyclophosphamide and tacrolimus, and anti-malaria drugs like hydroxychloroquine -- which can ease the fatigue, joint pain and skin rash that lupus commonly causes, according to the Lupus Foundation of America.

In some cases, doctors try a drug called rituximab, an IV medication designed to kill off certain B cells. Rituximab is approved to treat certain cancers and rheumatoid arthritis -- another autoimmune disease; but some lupus patients respond to the medication, too, the study authors said.

It's been unclear, though, why only certain lupus patients see benefits from rituximab, according to the researchers. Mauri said the new findings suggest a reason. People's response to rituximab may depend on whether they have normal activity in two genes related to interferon-alpha.

That, Mauri said, suggests that lupus patients should have gene testing before they're placed on rituximab. But, she stressed, "long-term studies -- where patients get tested before, during and after treatment -- are needed to prove that hypothesis unequivocally."

A rheumatologist who was not involved in the study agreed. "At this point, more work is needed, including looking at feasibility and cost issues," said Dr. Rosalind Ramsey-Goldman, a professor of medicine at Northwestern University Feinberg School of Medicine, in Chicago.

Ramsey-Goldman also agreed that the findings could eventually lead to new therapies, or point researchers in the direction of existing drugs for other conditions that could be "repurposed" to fight lupus.

The findings are based on blood samples from nearly 100 healthy volunteers and 200 people with lupus. Mauri's team found that lupus patients seemed to have an imbalance among three types of immune cells: B cells that produce antibodies; B cells that regulate inflammation; and cells that produce interferon-alpha.

Essentially, there is a lack of anti-inflammatory B cells, which leads to overproduction of interferon-alpha. That, in turn, boosts that number of antibody-producing B cells, the study found.

The root cause of it all remains a mystery, however, Mauri said.

And not all lupus patients would have this particular abnormality, according to Ramsey-Goldman. "SLE is probably a syndrome with multiple different immune system abnormalities," she said.

In general, Ramsey-Goldman explained, lupus is thought to arise from a combination of genetic susceptibility to autoimmune diseases and certain environmental factors.

Researchers still don't know what those factors are. But the suspects include certain infections, such as the Epstein-Barr virus, and on-the-job exposure to silica dust, according to the Lupus Foundation of America.

SOURCES: Claudia Mauri, Ph.D., professor, immunology, University College London, U.K.; Rosalind Ramsey-Goldman, M.D., Dr.Ph., professor, medicine, Northwestern University Feinberg School of Medicine, Chicago; March 8, 2016, Immunity, online
HealthDay
 

Who Me?

Well-Known Member
So they also need to figure out what subsets of SLE would benefit. And would this gene idea work for ME/CFS?

I wonder if they are concerned about possible chronic infections? Chronic infections seems to be a contraindication for patients with ME for rituximab.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
So they also need to figure out what subsets of SLE would benefit. And would this gene idea work for ME/CFS?

I wonder if they are concerned about possible chronic infections? Chronic infections seems to be a contraindication for patients with ME for rituximab.
There is enough gene work going on that I've gotta hope that if similar gene polymorphisms are present in ME/CFS they are going to show up. It's very possible that Fluge and Mella will be looking for them. If not them then hopefully Ron Davis.

Rituximab and chronic infections would be, I assume, a very bad idea.
 

Who Me?

Well-Known Member
Rituximab and chronic infections would be, I assume, a very bad idea.
I know there was chat about this 'elsewhere'. That's why I'm not jumping on the rtx bandwagon, why Fluge and Mella really need to figure out the subsets and why Rituximab is only going to be good for a % of PWME's and not the cure-all some try to lead us to believe.

I think I read somewhere that the people in the Norwegian study were referred by a neurologist so I can't imagine infections was a concern in that group.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I know there was chat about this 'elsewhere'. That's why I'm not jumping on the rtx bandwagon, why Fluge and Mella really need to figure out the subsets and why Rituximab is only going to be good for a % of PWME's and not the cure-all some try to lead us to believe.

I think I read somewhere that the people in the Norwegian study were referred by a neurologist so I can't imagine infections was a concern in that group.
I talked with Kogelnik quite a bit ago; he said a couple of people were having great responses. I got the impression that it was a bit hit and miss. I think Fluge and Mella are VERY interested in finding out which subsets benefit from Rituximab.
 

Who Me?

Well-Known Member
They may be interested but I'm not aware of anything being said about subsets.

It's going to take years. And even after all the trials are done you still have to find a doc to order it. Insurance to cover it. Who can afford the copay?

I'd still rather have ampligen.
 

Seanko

Well-Known Member
Rituximab certainly is not a cure for ME/CFS, it looks like it can help some people, guessing Fluge & Mella are trying to work out why this is.

Taking out a large chunk of your immune system comes with its risks. A recent Science Based Medicine article controversially implied that it could have made Whitney Dafoe's condition worse

Prof Claudia Mauri, one of the SLE paper authors, works at University College Lonodn (UCL) where the UK Rituxmab trail is being held. Her research summary contains a lot of familiar language on B & T cells with respect to Rheumatoid Arthritis.

Harnessing the regulatory properties of B cells in the therapy of autoimmune disease. B cells are conventionally regarded as effector cells capable of producing antibodies against invading pathogens or, in the case of autoimmunity, against self-antigens. However, a body of evidence is now emerging, suggesting that B cells also play a regulatory role in the evolution of immune responses, chiefly through their interactions with T cells.

I was amongst the first three groups in the world to identify a novel subset of B cells with strong suppressive capacity. Our original observation showed that activation of arthritogenic splenocytes with agonistic anti-CD40 gave a raise to a B cell population producing high levels of interleukin-10 (IL-10) and low levels of Interferon-? (IFN-?). Adoptive transfer of this B cell subset prevents disease development and ameliorates established arthritis (JEM, 2003).

In 2007 we have phenotypically identified regulatory B cells and demonstrated that they are contained within the transitional 2 B cells subset (T2-Breg). (JI 2007)(Trends in Immunol. 2008). We are currently translating the results from the experimental model to healthy individuals as well as to patients with rheumatoid arthritis and to patients with SLE and have recently "pinned down" the phenotype and the mechanisms of action.

Anti-TNF? therapy regulates CD4+CD25high T cells levels and function in rheumatoid arthritis. Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA).

We have demonstrated that regulatory T cells isolated from patients with active RA, although still anergic, were unable to suppress pro-inflammatory cytokines released by T cells and monocytes. In addition, these regulatory T cells lack the ability to convey a suppressive phenotype to neighbouring effector T cells.

The functional defect was not permanent, as suppressive activity was restored after anti-TNF? treatment. Furthermore, anti-TNF? treatment lead to a significant rise in the peripheral blood regulatory T cells of RA patients responding to this treatment, which correlated with a reduction in C Reactive Protein (CRP).

This work was done in collaboration with Prof. M. Ehrenstein and was the first study demonstrating that regulatory T cells are functionally compromised in RA, suggesting that modulation of regulatory T cells by anti-TNF_ therapy may be a further mechanism by which this disease is ameliorated (2004,JEM).

Consequentially, we have extended our previous observation and demonstrated that anti-TNF? blockade can lead to induction of regulatory T cells and has the potential for restoring tolerance (2007 JEM). Recently we have characterized the molecular defect of regulatory T cell in patients with RA and unravelled that the lack of suppression is due to an abnormal recirculation of CTLA-4, molecule important for the maintenance of tolerance.
 
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Seanko

Well-Known Member
Prof Julia newton of Newcastle University has written a paper on Rituximab on the liver auto-immune liver disease Primary Biliary Cirrhosis (PBC) which shares fatigue as a symptom.

RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial

Abstract

Introduction Primary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue.

This can be a particularly debilitating symptom, affecting quality of life and resulting in social isolation. Fatigue is highlighted by patients as a priority for research and patient support groups were involved in designing this trial.

This is the first randomised controlled trial to investigate a treatment for fatigue in PBC. The trial protocol is innovative as it utilises novel magnetic resonance spectroscopy (MRS) techniques as an outcome measure. The protocol will be valuable to research groups planning clinical trials targeting fatigue in PBC and also transferrable to other conditions associated with fatigue.
 

Seanko

Well-Known Member
In an interview with Prohealth, Prof Newton commneted on te PBC Rituximab trial & implications for ME/CFS

Rituximab trial
Q: You’re conducting a trial of Rituximab in primary biliary cirrhosis (PBC), a fatigue-associated autoimmune disease. There is a clear logic in administering Rituximab to these patients, but with CFS/ME not being recognized at all in some quarters, but certainly not yet recognized to be an autoimmune disease, will that make it harder to carry out a trial of Rituximab on ME/CFS in the future, or do you think this study on PBC, could lead you there?


“Absolutely, I think it depends a little bit on the extent of the benefit that we might see and whether or not we can convince a funding body to support the cost of the trial.

“If we do see any changes in fatigue we may well gain information that will help us understand the mechanism by which that improvement occurs. It is important to point out at this stage that the muscle and cardiac abnormalities that we have seen in patients with ME/CFS are exactly the same as those that we have seen in patients with PBC and we have published these studies too which is one of the reasons I am optimistic that the results of the PBC study might apply to the ME/CFS too.”
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
In an interview with Prohealth, Prof Newton commneted on te PBC Rituximab trial & implications for ME/CFS

Rituximab trial
Q: You’re conducting a trial of Rituximab in primary biliary cirrhosis (PBC), a fatigue-associated autoimmune disease. There is a clear logic in administering Rituximab to these patients, but with CFS/ME not being recognized at all in some quarters, but certainly not yet recognized to be an autoimmune disease, will that make it harder to carry out a trial of Rituximab on ME/CFS in the future, or do you think this study on PBC, could lead you there?


“Absolutely, I think it depends a little bit on the extent of the benefit that we might see and whether or not we can convince a funding body to support the cost of the trial.

“If we do see any changes in fatigue we may well gain information that will help us understand the mechanism by which that improvement occurs. It is important to point out at this stage that the muscle and cardiac abnormalities that we have seen in patients with ME/CFS are exactly the same as those that we have seen in patients with PBC and we have published these studies too which is one of the reasons I am optimistic that the results of the PBC study might apply to the ME/CFS too.”
I didn't realize that the muscle and cardiac problems were the same in PBC and ME/CFS! That's pretty exciting and now she's doing a Rituximab trial in PBC...If that trial works out - and I imagine that it will be done more quickly than our trials - that will be a good sign for ME/CFS.

I know Dr. Newton believes that autonomic nervous system problems are key to ME/CFS and PBC. She must then believe that the immune system is whacking the ANS - possibly though attacking the receptors in the blood vessels that open and close them (???)

I wonder when that trial will finish up....
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I know there was chat about this 'elsewhere'. That's why I'm not jumping on the rtx bandwagon, why Fluge and Mella really need to figure out the subsets and why Rituximab is only going to be good for a % of PWME's and not the cure-all some try to lead us to believe.

I think I read somewhere that the people in the Norwegian study were referred by a neurologist so I can't imagine infections was a concern in that group.
It's a subject I that Dr. Klimas worries about; in whom do you suppress the immune system and in whom do you activate it? I believe Dr. Peterson has worries about this with regards to Rituximab. I would be shocked if both subsets weren't present in ME/CFS.
 

Who Me?

Well-Known Member
I could not get treatment for psoriasis because my immune system is a mess. I can't imagine this would be good for me. Not to mention my infections.
 

weyland

Well-Known Member
Taking out a large chunk of your immune system comes with its risks. A recent Science Based Medicine article controversially implied that it could have made Whitney Dafoe's condition worse
That article was total garbage. It's pointless to speculate anecdotally about one patient whose illness was apparently already progressing rapidly regardless of treatment. The author of that article doesn't "believe" in CFS, so let's please not give her any more attention.

Let's focus instead on any adverse effects or harms reported as part of the ongoing scientifically rigorous trials. I'm not saying rituximab is safe by any means, but it doesn't do any good to blow the dangers out of proportion.
 

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