BIG NEWS: CFS remissions on Rituximab suggest autoimmune aspect – for subset at least

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Following is an explanatory news release from PLoS ONE – the journal that published these intriguing research findings on Oct 19; plus a link to the full text article, a summary abstract of the key findings and the description of the trial.

PLoS ONE News Release:

Chronic fatigue syndrome (CFS) may be alleviated by the anti-cancer drug Rituximab, suggesting that the source of the disease could lie in the immune system, according to a new study published Oct. 19… Uncertainty about the cause of CFS, which is characterized by extreme, unexplained exhaustion, among other symptoms, has led to much debate, but the authors of this recent study believe they may have found the answer.

The work, led by Drs. Oystein Fluge and Olav Mella of Haukeland University Hospital in Norway, was initiated when the researchers noticed a patient with both chronic fatigue syndrome (CFS) and Hodgkin’s lymphoma who showed marked recovery from CFS symptoms upon treatment with chemotherapy.

The investigators reasoned that the effect could be mediated through B-lymphocyte depletion, and to further investigate this connection they conducted first a pilot case series, and then a double-blind, placebo-controlled phase II trial with 30 CFS patients, and found that the Rituximab treatment was associated with significant, but generally transient, improvement in CFS symptoms.

Rituximab is a B-lymphocyte depleting agent. It acts as an antibody against a protein found primarily on the surface these cells, which are a component of the immune system.

According to the authors, “the delay of clinical responses after the initial and rapid B-cell depletion suggests to us that CFS/ME, which is often preceded by an infection, may be a form of autoimmune disease in which B-cells are important”. Thus, this study reveals a potential new direction for CFS research.

Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study – Source: PLoS One, online Oct 19, 2011

By Oystein Fluge, Olav Mella, et al.

[Note: the full text of this article is available online at  – (scroll down).]

Background: Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

Methods and Findings: In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients.

The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003).

Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44). Four Rituximab patients had clinical response durations past the study period.

General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative.

There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.

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. The present findings will impact future research efforts in CFS.

Trial registration: NCT00848692 [See trial description at]

Source: PLoS One, online Oct 19, 2011. Fluge O, Bruland O, Risa K, Storstein A, Kritoffersen EK, Sapkota D, Naess H, Dahl O, Nyland H, Mella O. Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway; Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Immunology and Transfusion Medicine, Haukeland University Hospital, and The Gade Institute, University of Bergen, Bergen, Norway; Institute of Internal Medicine, Section of Oncology, University of Bergen, Bergen, Norway.

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11 thoughts on “BIG NEWS: CFS remissions on Rituximab suggest autoimmune aspect – for subset at least”

  1. aidanwalsh says:


  2. says:

    Fascinating. Totally in agreeance with the challenge in the immune system. Trick is diagnosing what is causing the disturbance in the first place. After living with CFS for many years and slowly recovering I can guarantee hidden infection causing the immune to over react. The testing ability for bacteria, parasite, virus, candida need improving. I do not believe the immune system just reacts to nothing, there will be something hidden. It’s just being lucky enough to find it. Very glad the drugs are helping but it will be a band aid solution. You must keep digging to find the trigger, that’s what I did, and slowly one by one they showed up and were removed. Good luck to all 🙂

  3. rongraves says:

    Hate to rain on anyone’s parade, but results from a test population of just 30 individuals is as close to statistically meaningless as it gets.

    An indicator that very much more research is needed – nothing more.

  4. IanH says:

    This result could be predicted if you believe ME is an immunological dysfunction. I can predict that if dimethyl fumarate was used you would lso have a similar result in ME.

    Dimethyl Fumarate is one of the only drugs activating the Nrf_2 pathway.

    Reactive oxygen species (ROS) can damage biological macromolecules and are detrimental to cellular health. Enzymes are involved in the Phase II detoxification of xenobiotics to reduce cellular stress include glutathione transferases, quinone reductase, epoxide hydrolase, heme oxygenase, UDP-glucuronosyl transferases, and gamma-glutamylcysteine synthetase. Expression of these genes protects cells from oxidative damage and can prevent mutagenesis and cancer. Transcription of these enzymes is coordinately regulated through antioxidant response elements (AREs). Nrf2 (NF-E2-related factor 2) and Nrf1 are transcription factors that bind to AREs and activate these genes.

    Inactive Nrf2 is retained in the cytosol by association a complex with the cytoskeletal protein Keap1. Cytosolic Nrf2 is phosphorylated and translocates into the nucleus in response to protein kinase C activation and Map kinase pathways. In the nucleus, Nrf2 activate genes through AREs by interacting with transcription factors in the bZIP family, including CREB, ATF4 and fos or jun. Nrf2 activation of genes is opposed by small maf proteins, including MafG and MafK, maintaining a counterbalance to Nrf2 and balancing the oxidation level of the intracellular environment.

    ME (CFS) has been excessively mis-diagnosed because the symptoms are so similar to many pathologies. The poster suggesting a relationship with spinal pathologies is pointing this out. But, no, ME has no relationship to Chiari Malformation even though many people with CM were diagnosed with CFS before the CM was picked up on MRI. Similarly people with spinal trauma who develop fibromyalgia can also be confused with ME. Fibromyalgia is not ME but people with ME can develop FM if they have unremitting pain sources which can be amplified by their ME.

  5. it's m.e, NOT cfs! says:

    At least call it CFIDS! The CDC site has outdated information on “CFS”, and it is doing us no good. CFIDS is an auto-immune disease with dysfunction in the b-cells as well as the natural killer cells.

  6. Laehcar says:

    Autoimmunity is known to have a genetic component and tends to cluster in families as different autoimmune diseases. Even though there is some universally accepted knowledge about autoimmunity and its victims who are mostly women, autoimmunity has yet to be fully embraced by the medical community. Autoimmune diseases strike women three times more often than men and CFS is diagnosed two to four times more often in women than in men.

    In my own quest, to find answers regarding CFS (25+ year sufferer), which I have believed, for a very long time to be an autoimmune illness, I became very interested in the immune systems involvement in my condition. By calming my immune system with antihistamines (and a list of other suppressants/calming agents of the immune system), my condition has greatly improved.

    1. nl2 says:

      How does a person calm the “immune system”? With what type of products? I’m looking for ways to boost my immune system especially during cold winter months since I catch other peoples temporary illnesses such as cold, flu, stomach flu, etc. I don’t need another illness to battle because it feels like I’m slowly dying! It’s terrible….. I also believe that there is a “hidden infection” in our fragile bodies!

      Please keep the research going!!! We need answers to this monsterous illness..

    2. gspecilk236 says:

      Could you please expand on your antihistamines/suppressants treatments? I’d love to know and share with my doc. Thank you!

  7. Laehcar says:

    One day, it will be proven, that having a genetic
    predisposition, to develop an autoimmune illness and
    an environmental trigger is the cause of CFS. In some
    susceptible people that trigger may very well may be a
    virus, or infection. In others, some sort of
    stimulation, or change in the immune system (adverse
    vaccination reactions, a chemical poisoning, or a
    trauma eg surgery, accidents), something that causes
    the immune system to go haywire in genetically,
    predisposed individuals; those who were born with more
    sensitive immune systems than the average person.

  8. richvank says:

    Hi, all.

    I want to express my view that the fact that some patients recovered from ME/CFS after treatment with Rituximab does not necessarily mean that ME/CFS is an autoimmune disorder.

    In addition, while small elevations in autoantibodies have been observed and reported in ME/CFS patients in the past, this also does not necessarily mean that ME/CFS is an autoimmune disorder.

    In my view, in this study the role of Rituximab, which knocks out the B lymphocytes, was to lower the inflammation that is promoted by these lymphocytes in ME/CFS, because of the shift to Th2 in this disorder and the usual low level of cortisol, which normally suppresses inflammation. Lowered inflammation means lowered oxidative stress, which is a component of inflammation. Lowered oxidative stress means lowered demand on glutathione. I suspect that the glutathione levels were able to recover enough in some patients to break the vicious circle mechanism involving vitamin B12 functional deficiency, a partial block in the methylation cycle, and draining of folates from the cells, and the immune system was able to shift back to a normal balance between Th1 and Th2 because of the improved glutathione status. Then, when the B cells came back, inflammation was under better control.

    In those who did not experience longterm recovery, apparently the inflammation continued to be severe enough to re-establish the glutathione depletion and the vicious circle.

    In those who did not experience even temporary benefit from treatment with Rituximab, I suspect that other factors were continuing to hold down the glutathione, so that even though the inflammation was suppressed, glutathione continued to stay too low to break the vicious circle. Toxins would be major suspects in these cases, I think.

    Best regards,


  9. IanH says:

    We really do need to take people with MCS seriously and examine the immunological consequences of toxins in common products with ubiquitous exposure. There is a tendency to ignore the genetic differences in people when doing such research, the consequence of which is often annulling of significant results.

    I am certain that abnormalities in toxin metabolism is a big factor in the cause of ME, not just an effect.

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