Advertisement
Research Article

Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

  • Øystein Fluge mail,

    oystein.fluge@gmail.com

    Affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway

    X
  • Ove Bruland,

    Affiliations: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway, Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    X
  • Kristin Risa,

    Affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway

    X
  • Anette Storstein,

    Affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway

    X
  • Einar K. Kristoffersen,

    Affiliation: Department of Immunology and Transfusion Medicine, Haukeland University Hospital, and The Gade Institute, University of Bergen, Bergen, Norway

    X
  • Dipak Sapkota,

    Affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway

    X
  • Halvor Næss,

    Affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway

    X
  • Olav Dahl,

    Affiliations: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway, Institute of Internal Medicine, Section of Oncology, University of Bergen, Bergen, Norway

    X
  • Harald Nyland,

    Affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway

    X
  • Olav Mella

    Affiliations: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway, Institute of Internal Medicine, Section of Oncology, University of Bergen, Bergen, Norway

    X
  • Published: October 19, 2011
  • DOI: 10.1371/journal.pone.0026358

Reader Comments (11)

Post a new comment on this article

Rituximab-driven Improvement of CFS Symptoms: Suppression of Autoantibody-mediated Autoimmunity or Enhanced Cell-mediated Immunity Following B Cell Depletion?

Posted by Pawel on 25 Oct 2011 at 14:04 GMT

In this interesting and important study, Fluge and colleagues report on the improvement of self-reported Fatigue score in 10/15 (67%) patients with Chronic Fatigue Syndrome who received treatment with (B cell-depleting) Rituximab . While the Authors indicate that their results are consistent with the (antibody-mediated) autoimmune pathogenesis of CFS, an alternative explanation of their findings may be that the depletion of B cells helped to improve CFS symptoms by enhancing cell-mediated (type-1) immunity that can be adversely affected by activated B cells.

The phenomenon of enhanced Th1 immunity following B cell depletion has been previously-demonstrated in mouse (Moulin V et al., 2000. B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation. J Exp Med. 192(4):475-82; Reviewed in Kalinski & Moser. 2005. Consensual immunity: success-driven development of T-helper-1 and T-helper-2 responses. Nat Rev Immunol. 5(3):251-60).

Such alternative explanation (enhanced Th1 or Th17 responses in the patient receiving Rituximab would be compatible with the currently-reported exacerbation of psoriatic lesions in the two patients who had previously documented psoriasis.

Evaluation of the Th1 and Th17 immunity in correlation with the changes in the Fatigue score following anti-CD20 treatment would help to address this possibility.

Pawel Kalinski,
Pittsburgh, PA

No competing interests declared.

RE: Rituximab-driven Improvement of CFS Symptoms: Suppression of Autoantibody-mediated Autoimmunity or Enhanced Cell-mediated Immunity Following B Cell Depletion?

Ingeli replied to Pawel on 27 Oct 2011 at 07:31 GMT

Kalinski, what do you think could be the mechanisms for the symptom improvement in ME patients related to a possible enhanced Th1 and Th17 response?

Inge Lindseth
Oslo, Norway

No competing interests declared.

RE: Rituximab-driven Improvement of CFS Symptoms: Suppression of Autoantibody-mediated Autoimmunity or Enhanced Cell-mediated Immunity Following B Cell Depletion?

Fluge replied to Pawel on 31 Oct 2011 at 17:37 GMT

To the Editor,

We thank dr. Kalinski for his comment and suggestion for an alternative mechanism for the observed improvement of selfreported Fatigue-score during follow-up. In our study [1], the responses on CFS/ME related symptoms were delayed compared to the rapid B-cell depletion following start of Rituximab infusions. The responders started to improve between 2 -7 months after intervention, but the differences between the Rituximab and Placebo groups were most evident between 6 – 10 months. Generally, all CFS/ME related symptoms improved when the responses occurred.
This delay of clinical improvement relative to rapid B-cell depletion is one observation that made us speculate that CFS/ME could be a form of autoimmune disease and that the effects could be mediated at least in part through gradual elimination of disease-specific autoantibodies. Other aspects that could indicate such a mechanism in CSF is the majority of female gender in CFS/ME, the reported genetic predisposistion [2], and frequencies of other autoimmune diseases in patients or first-degree relatives (in our study).

Importantly, this is a hypothesis for further work, and we have not demonstrated that CFS/ME is an autoimmune disease. In the discussion, we have also mentioned alternative mechanisms such as influence on B-cell antigen presentation to T-cells, effects on other players in the immune systen such as dendritic cells, cytokine changes, or elimination of B-lymphotropic viruses.
The alternative mechanism proposed by dr. Kalinski, in which the symptoms could be maintained through a sustained imbalance in Th1 and Th2 responses, with restoration towards enhanced Th1 cell mediated immunity after elimination of activated B-cells, is certainly one possibility that should be investigated. This postulate was proposed in a hypothesis article on mechanisms for the related Gulf War Syndrome in 1997 [3]. We will try to pursue his suggestions in our further research.

Certainly, the immunological disturbances behind the CFS/ME disease will turn out to be complicated, and a joint effort will be needed to elucidate the pathogenesis. We believe that the hypotheses for further research should also include our observation that in a subset of CFS/ME patients B-cell depletion targets a mechanism for symptom maintenance, either directly or indirectly.


1. Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, et al. (2011) Benefit from B-cell depletion using the monoclonal anti-CD20 antibody Rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One.
2. Albright F, Light K, Light A, Bateman L, Cannon-Albright LA (2011) Evidence for a heritable predisposition to Chronic Fatigue Syndrome. BMC Neurol 11: 62.
3. Rook GA, Zumla A (1997) Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile? Lancet 349: 1831-1833.


Øystein Fluge and Olav Mella
Department of Oncology and Medical Physics
Haukeland University Hospital

Competing interests declared: Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for chronic fatigue syndrome. Family members of WO2009083602 A1 are pending, as well as granted US 12/348024. The two authors ØF and OM are named as inventors in these applications.