heard about it through Invest in ME)
Correspondence on Rituximab study ["Benefit from B-Lymphocyte
Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue
Syndrome. A Double-Blind and Placebo-Controlled Study"]
[I've given each sentence its own paragraph to try to increase
readability. Refer to original for original formatting.
Table for harms-related data (=3Dadverse events): http://bit.ly/yzUI2c i.e=
.
http://www.plosone.org/article/slideshow.action?uri=3Dinfo:doi/10.1371/jour=
nal.pone.0026358&imageURI=3Dinfo:doi/10.1371/journal.pone.0026358.t005
Tom]
---------------
http://bit.ly/zxOxfA
i.e.
http://www.plosone.org/annotation/listThread.action?inReplyTo=3Dinfo:doi/10=
.1371/annotation/b3d77c11-5f3c-447c-ae74-a38aa62cf101&root=3Dinfo:doi/10.13=
71/annotation/b3d77c11-5f3c-447c-ae74-a38aa62cf101
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.
--------
(I've given each sentence its own paragraph to increase readability)
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=92 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=3D0.13.
Could it be that Wensaas=92 hypothesis on the mechanisms of CFS symptom
maintenance has influenced his judgment?
=D8ystein 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 =D8F and OM are named as inventors in these applications.
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