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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

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  • 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

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  • Kristin Risa,

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

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  • Anette Storstein,

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

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  • Einar K. Kristoffersen,

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

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  • Dipak Sapkota,

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

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  • Halvor Næss,

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

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  • 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

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  • Harald Nyland,

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

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  • 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

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

Reader Comments (11)

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Was the blinding in this study effective?

Posted by WensaasKA on 09 Feb 2012 at 06:54 GMT

The rituximab study offers important contributions to the understanding of the mechanisms and possible treatment in CFS. One major issue that needs to be addressed and resolved before initiating larger studies is whether the blinding in this study was successful. Did the patients anticipate which treatment they received?

Previous studies have shown effect of cognitive behavioral therapy on the symptoms of CFS (1, 2), indicating that in long-standing disease and loss of function complex mechanisms are involved. It is important to ensure that blinding in this study was effective, to reduce the possibility for cognitive mechanisms accounting for the effect.

Seven cases of adverse effects are reported, all in the Rituximab-group and it seems that this relates to seven different patients. Onset of adverse effects occurred synchronous with or just before the effect on the CFS symptoms in five of these patients. It is stated that none of the five patients without effect in the Rituximab-group experienced adverse effects.

One could hypothesize that anticipation of active treatment may have a beneficial effect on CFS symptoms, and the reported results may be re-analyzed accordingly: Among the 30 patients included in the study there is one group of seven patients that experienced adverse effects and one group of 23 that did not. In the "adverse effects" group all seven reported improvement, while in the "no adverse effects" group five out of 23 reported improvement. This effect in the "adverse effects" group is significantly different from the effect in the "no adverse effects" group (p<0.001).


1. Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev. 2008:CD001027.

2. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011;377:823-36.


Knut-Arne Wensaas
Researcher II, Ph.D, MD
Research Unit for General Practice, Uni Research, Bergen, Norway

No competing interests declared.

RE: Was the blinding in this study effective?

Fluge replied to WensaasKA on 09 Feb 2012 at 22:17 GMT

Dr. Wensaas questions the blinding of the study and suggests that the data should be reanalyzed comparing the clinical response rates in patients with reported side-effects and in patients with no reported side-effects during follow-up. He suggests that cognitive mechanisms due to anticipation of having received active drug could be operative and account for the observed effects. There are several statements in his comment that need to be commented.
First, for some unknown reason, Wensaas has omitted the infusion-related complaints during the first 24 hours from his grouping of patients with or without side-effects. Side-effects occurring during or early after infusion are probably more suggestive than those occurring late in indicating group allocation (Rituximab versus Placebo) to the patient. There were five and four reported complaints the first 24 hours after infusion in the Rituximab and Placebo groups, respectively, and the only early complaint seemingly specific for the Rituximab group was slight itching, reported by two patients.
Also, again for an unknown reason, Wensaas decided to omit from his analysis the two patients in each group reporting CFS worsening the first two months after intervention.

It is not correct that the onset of adverse effects occurred synchronous with or just before the effect on the CFS symptoms in five of the patients in the Rituximab group. Our statement in the manuscript text that these symptoms occurred synchronously with responses was not meant to suggest that the side-effects began immediately before or at the same time as the clinical responses.
The patient with low back pain and balanitis reported at 5-7 months had his initial clinical response starting from 3 months after intervention.
The patient with irregular menstrual bleeding the first two months experienced moderate clinical response on CFS symptoms from 5 months after intervention.
The two patients with some worsening of psoriasis from 2 months after treatment experienced the clinical responses starting to occur from 7 months and 6 months respectively, i.e. with a relatively long time interval before CFS improvement.
However, the two patients feeling uneasy and sleepless reported these symptoms just prior to or at the same time as the clinical responses.
Importantly, these described symptoms during follow-up are not usual side-effects from Rituximab treatment in other diseases, but were reported by the CFS patients during follow-up. Thus they did not suggest to the doctor or patient which treatment had been given. For instance, irregular menstrual cycle is not an uncommon symptom among women with CFS. Slight acne is not a common or specific symptom associated with Rituximab treatment. We have not observed transitory balanitis and lower back after Rituximab when treating several hundreds of lymphoma patients with Rituximab. Because these symptoms are unusual in other patients after Rituximab treatment, we suggest that they might partly be related to the effects of B-cell depletion on the CFS disease, rather than be direct side effects from Rituximab.

We do not believe that dr. Wensaas is correct in his interpretation. The clinical improvements observed in the Rituximab group vary from no response (1/3), to moderate response, and to major response, where some of the patients report no (or almost no) remaining CFS symptoms. We do not believe that the latter could occur from expectation of improvement alone. The SF-36 data also suggest that the clinical improvements achieved by responders are of clinical significance.
If cognitive mechanisms were the mechanism for the observed differences in the Rituximab and Placebo groups, why should then 8 out of 10 responders in the Rituximab experience a clear relapse of their CFS symptoms?
We also question Wensaas’ reason for selecting given side effects and omitting others in his statistical analysis, which we think is misleading to the reader. In the Rituximab group 9 out of 15 patients reported a total of 14 complaints or side-effects during follow-up. In the Placebo group 6 out of 15 patients reported a total of 6 complaints or side-effects.

A 2x2 table exploring the relationship between reported side-effects and clinical responses, should of course include both the early complaints and the CFS symptom worsening the first months after intervention and not only selected late side-effects (shown in table 5 in the article). Such a table would then include the following data: a total of 15 out of 30 patients reported any side-effects during follow-up. Out of these 15 patients, 8 had a clinical response, and 7 had no response. Out of 15 patients with no reported side-effects during follow-up, 4 had a clinical response and 11 had no response. Chi-square statistics for this table would give p=0.13.
Could it be that Wensaas’ hypothesis on the mechanisms of CFS symptom maintenance has influenced his judgment?

Øystein Fluge and Olav Mella

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.

RE: RE: Was the blinding in this study effective?

WensaasKA replied to Fluge on 15 Feb 2012 at 23:19 GMT

In a blinded study it is essential that the blinding is effective, especially in a trial where the outcome is based on patients’ symptoms.
Fluge and Mella conclude that the blinding in this study was good (in their response to van der Meer et al), but they also report that they did not ask the patients which drug they thought they had been given. Their conclusion is questionable, and I have proposed one alternative way of analyzing the data that challenges the main results. Fluge and Mella argue against my analysis, and show that other approaches would give different results. However, they evade my main concern; whether the blinding in this study was effective.
Positive effects of Rituximab must be confirmed in other studies before this treatment should be implemented in clinical practice. I hope that further steps are taken do assess the effectiveness of the blinding in subsequent studies, thereby strengthening the validity of the results.

Knut-Arne Wensaas

No competing interests declared.

RE: RE: RE: Was the blinding in this study effective?

Fluge replied to WensaasKA on 20 Feb 2012 at 17:00 GMT

Dr. Wensaas claims that we evade his concern on whether the blinding of the study was effective. His alternative hypothesis is that the observed benefit from B-cell depletion was a result of cognitive mechanisms caused by an association between observed side-effects and clinical response (i.e. the patients guessed that thay had been given active drug and thus reported response).
In our reply to his first comment, we thorougly explain why the assumptions for this alternative analysis on the relationship between side-effects and response are wrong (see above). Therefore, we have not evaded his main concern. We have argued against the premises for his analysis. We have still not received an answer to why he selected some of the reported side effects and omitted others in his analysis.

In an interventional study using active drug versus placebo, there will always be the possibility that side-effects may suggest group belonging to the patient. There are no means to avoid this completely. In the present study we believe that efforts were made to minimize this. There was no study inquiry into what treatment the patients thought they had received. However, spontaneous remarks by patients often proved wrong when they were informed on group allocation at study end. The complete data in Table 5 in the manuscript also shows that there was no significant association between reported side-effects and clinical response.

We have previously stated that more studies are necessary before B-cell depletion could be considered as a therapeutic option in selected patients with CFS/ME. Our ongoing open-label phase-II study (NCT01156909) with Rituximab induction and maintenance (new infusions after 3, 6, 10 and 15 months), in which 28 patients have been included and all patients now have been observed at least 12 months, will provide more data. The reason for performing an open-label study now, is to gain knowledge on the relationship between clinical response (and side-effects) and prolonged B-cell depletion. The information from this study is intended to be a basis for designing a protocol for a new randomized, double-blind, placebo-controlled, multicentre phase-III study.

Due to limitations in the PLoS One study, which have been thoroughly described in our manuscript and further explained in detail in our previous replies to comments, our data need to be confirmed in new clinical studies. Therefore, at present patients should not be treated with Rituximab for CFS/ME outside clinical studies, because we need to know more on the response patterns and possible unknown side-effects in this patient group.
However, we do not believe that dr. Wensaas concern is among the possible limitations when interpreting the data.

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.

RE: Was the blinding in this study effective?

tkindlon replied to WensaasKA on 23 Feb 2012 at 01:27 GMT

Dr. Wensaas says that: "Previous studies have shown effect of cognitive behavioral therapy on the symptoms of CFS (1, 2), indicating that in long-standing disease and loss of function complex mechanisms are involved. It is important to ensure that blinding in this study was effective, to reduce the possibility for cognitive mechanisms accounting for the effect."

It is interesting to note that the effects of cognitive behavioral therapy (CBT) for CFS on objective markers is far from clear. For example, in the study quoted (the PACE Trial) (2), there was no difference between the CBT + specialist medical care (SMC) and the SMC alone in the change in the only measure reported that could be described as an objective measure, the 6-minute walking distance (6MWD). Both had poor outcomes: 354m and 348m respectively (the SMC result was numerically 1.5m better when baseline factors were included). References equations predict a value of 644m for this cohort (3,4).

A review of three Dutch CBT studies found that although they reported improvements in fatigue (as well as some other measures in individual studies), there was no improvement in physical activity levels compared to the control group. So the effects on functioning are far from clear. Unfortunately we don't have data from actometers from the PACE Trial (2) because, according to the investigators, "although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial." (6)

It is also useful to highlight that there is no blinding in CBT studies, while it is probably unlikely that every patient in the PLoS ONE Rituximab study knew which arm of the trial they were on due the side effects, as some didn't report any.

Finally, it's worth highlighting that a study previously found that positivity did not result in a reduction in fatigue levels in CFS. (7)

1. Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev. 2008:CD001027.

2. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011;377:823-36.

3. Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am. J. Respir. Crit. Care Med., 1998; 158: 1384–1387

4. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Bulletin of the IACFS/ME. 2011;19(2):59-111. http://www.iacfsme.org/BU...

5. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Aug;40(8):1281-7. Epub 2010 Jan 5.

6. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R, for the PACE trial management group Response to comments on “Protocol for the PACE trial” http://www.biomedcentral....

7. Hyland ME, Sodergren SC, Lewith GT. Chronic fatigue syndrome: the role of positivity to illness in chronic fatigue syndrome patients. J Health Psychol. 2006 Sep;11(5):731-41.

Competing interests declared: I am the information officer of the Irish ME/CFS Association. All my work for the Irish ME/CFS Association is voluntary (i.e. unpaid).

Typo RE: RE: Was the blinding in this study effective?

tkindlon replied to tkindlon on 23 Feb 2012 at 01:49 GMT

Oops, I left out my name (Kindlon T.) in reference 4 - I'm partly posting this in case somebody thought I had deliberately left it out to hide that it was my paper.

Competing interests declared: I am the information officer of the Irish ME/CFS Association. All my work for the Irish ME/CFS Association is voluntary (i.e. unpaid).