"We have a series of comments to this paper. Firstly, an important methodological question with regard to the blinding of the study. It is likely that patients can sense whether they received RTX, either during or after the infusion, did the investigators check for this by querying the patients as to which arm of the study they believed they were in (before unblinding)?"

Table 5 on page 11 of the paper shows infusion related complaints in both groups. The interesting thing about this table is how similar were the reactions at the time of infusion between the Rituximab and the control groups.

"Secondly, we have a series of methodological concerns regards the measurements of fatigue: we feel the fatigue change score is conceptually less valid than a contemporaneous rating. In addition, the psychometric characteristics of the test used are unknown to us. "

It is a failing of this small exploratory study that it does not use objective outcome measures, such as an actimeter to measure actual physical activity. However, that is a failing with many papers on this illness group. I refer you to the recent PACE⁽¹⁾ trial paper which similarly used SF 36 scores for entry and exit criteria.


"Our greatest concern is the statement by the investigators that they want to proceed with an open label follow up study, instead of a larger, blinded and placebo-controlled RCT. Investigators, clinicians and patients should learn from the XMRV demise, in which many patients were allowed to use antiretroviral treatment on the basis of scanty and - as we know now - spurious data [4,5]. The data in the Fluge paper are far from conclusive, and it is much too early to start use of this expensive and potentially harmful drug in patients with CFS, in settings other than that of high quality RCTs. It should be emphasized that the authors have tended to downplay the potential harms , including the uncommon but important risk of progressive multifocal leukencephalopathy, whereas on the side of notional benefit they overestimate the effect size and power of their study."

I do not believe the authors are encouraging patients to undergo this therapy, rather the authors are now going forward with a further, larger trial. Patients with CFS are known to kill themselves rather than bear further years of suffering - witness Lynn Gilderdale - but I very much doubt they are going to set up home infusions. Again, the PACE trial, much vaunted by the signatories of this comment was de facto an open label study. The therapies recommended by that study on much more spurious grounds are also dangerous to patients. It is time that ME aka CFS was seen as the serious physical disease it is. It is time to study the science, not the preconceptions of outdated paradigms.


1) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial: PD White et al, Lancet 2011

Jane Clout

The criticism made here contains several errors. There is nothing peculiar about the late response. It is to be expected. I was responsible for both the phase I and the proof of concept phase II (NEJM 2004) studies in rheumatoid disease, which formally established the validity of B cell depletion in autoimmune disorders. From the very outset in 2000 we reported that responses could take many months to develop, in line with autoantibody decline. An partial early response element was usually seen as well but was consistent with adjuvant use of corticosteroid or other agents.
I am not aware of any hard evidence for rituximab working in autoimmune disorders not mediated by autoantibodies. Where there have been proper trials, as for psoriatic arthropathy, the results have been clearly negative as far as I am aware. The suggestion that rituximab works through an action on antigen presentation is pure speculation for which I cannot think of any positive supportive evidence and there is much unsupportive evidence, including the very common very slow response kinetics that follow antibody decline. This is an idea popularised before we actually had any data and still often repeated in reviews despite the wealth of evidence against. It is hard to see how killing B cells at day one would affect antigen presentation by B cells six months later, putatively responsible for further decline in inflammation to nine months. The trial's authors give the account that is by far the most consistent with the data - that benefit occurs as short lived plasma cells die off and autoantibodies decline but that benefit is often incomplete as expected from the existence of long lived plasma cells and continued lower levels of antibody. The absence of a clearly defined autoantibody population in this particular group is not in any way surprising. It is likely to be immunopathologically heterogeneous and new autoantibodies are being found all the time.

Jonathan Edwards
Professor Emeritus, UCL

Dr Van der Meer and colleagues raise questions about the outcome measures used in this trial (1,2). However it should be acknowledged that the outcome measures used in many trials that have previously been published in the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) field could also be said to be problematic.

The trials I am most familiar with (as I had as I have had several letters published concerning them (3) and have a paper under the review on them) are trials of cognitive behavioural therapy (CBT) and graded exercise therapy (GET), which are often described as evidence-based treatments for the condition. However a closer examination of the outcome measures used show there are a lot of problems with the outcome measures employed in trials of these interventions in particular.

Van der Meer and colleagues are concerned that there is a chance that some of the patients in the Rituximab leg guessed which treatment they were on. However, with CBT and GET trials, there is no blinding of patients and given the outcome measures are generally subjective, along with the nature of the interventions (CBT and GET), response biases are quite possible, indeed perhaps more likely than not.

Also in the Fluge et al study, there is reason to believe that many patients might experience some benefit from the particular placebo used, saline infusions, due to hypovolemia in the condition and autonomic dysfunction (4). Indeed there is currently a trial testing its use for CFS (5). So some patients in the placebo arm could conceivably think they were receiving the active therapy.

Van der Meer and colleagues question the main outcome measure, the fatigue measure. However, the fatigue measures previously used in trials of interventions for ME/CFS have been far from perfect. Also, the name does not get across the full extent of what it measures: "Fatigue score was calculated as the mean of the four symptoms: Fatigue, Post-exertional exhaustion, Need for rest, Daily functioning."

It is true to say that the Chalder fatigue scale, often used in the ME/CFS field, has been validated in one way, to define "fatigue caseness" (6). This means that a score of four or more using bimodal scoring equals a fatigue case. However the measure is often not employed in this way (i.e. categorically) but as a linear scale, despite the fact that the bimodal scoring system clearly has ceiling problems associated with it. Likert scoring (0-3 for each of the 11 items i.e. the range of scores from 0-33) is also sometimes used but it is not validated and also suffers from ceiling problems for individual items. In the recent UK£5m PACE Trial, bimodal scoring (a score >=6, an unvalidated threshold) was used for recruitment, a different form of bimodal scoring was listed in the trial protocol's primary measures (one of the two options employed the validated fatigue caseness criteria) but in the results paper, the data for the validated Chalder fatigue measure (i.e. fatigue caseness) was not reported and the authors switched to the (unvalidated) Likert scoring system as one of the primary outcome measures (7,8).

In a review of three Dutch CBT studies (the form of CBT was designed to encourage increased activity), it was found that although patients reported improved fatigue levels over the control group, there was no difference between the CBT group and the controls on the objective outcome measure, motion sensing devices, suggesting fatigue measures may be problematic for such trials (9).

Those involved in the PACE Trial seemed to recognise the potential problems with subjective outcome measures as initially they planned to use motion sensing devices before the interventions and on completion, although unfortunately before the trial commenced they decided to drop the use of actometers as an outcome measure but still use them as a baseline measure (10).

Innovation can be useful; sometimes researchers can be conservative, using outcome measures simply because they've been used in other trials. However, that does not mean that previously used outcome measures are perfect or even fit for purpose. It is also interesting to note that in the three Dutch CBT studies covered by the Wiborg review (i.e. the review which found there was no difference in objectively measured activity), improvements in other outcome measures had been reported.

Fluge and colleagues also used other measures apart from their new Fatigue score: "The Pain score was calculated as the mean of the two pain symptoms assessed to be characteristic for the patient (if pre-treatment level >=5, among Muscle pain, Joint pain, Headache, Cutaneous pain). The Cognitive score was the mean of the three symptoms: Concentration ability, Memory disturbance, Mental tiredness. The ‘‘Other symptoms score’’ was derived from the mean of the two symptoms assessed as characteristic for the patient’s CFS disease, among those with the highest self-reported pre-treatment level. Also, the patient’s self-reported overall interpretation of their CFS disease was recorded (‘‘CFS overall score’’). The Fatigue score, Pain score, Cognitive score, ‘‘CFS overall score’’, and ‘‘Other symptoms score’’, were plotted every second week, for each patient in separate diagrams."

These are indeed new measures but are not necessarily inferior to ones used in previous ME/CFS trials. Also it is good to see that a variety of symptoms are measured as there has been a lot of focus on one specific symptom, fatigue, in previous trials even though patients experience a wide variety of symptoms (11). Fluge and colleagues also measured symptoms very regularly which might be more useful at assessing symptoms than using a single time-point, especially considering the fluctuating symptoms one can find in ME/CFS.

The PACE Trial, the largest triel in the field so far, showed that graded activity-oriented CBT and GET's effects are not large on average especially when one looks at the results of the 6 minute walking tests (8). Clearly these interventions should not be seen as sufficient therapies for ME/CFS.

I hope these innovative researchers (Fluge and colleagues) will maintain their interest in the field.

Tom Kindlon


References:

(1) Van der Meer Jos WM, Lloyd Andrew, Buckland Matthew, Miller Alistair, Buchwald Dedra, Angus Brian. Rituximab in CFS; more research needed. <http://bit.ly/rrlmqQ>

(2) Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Naess H Dahl O, Nyland H, Mella O, benefit from B-lymphocyte depletion using the anti-CD20 antibody Rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PloS One 6:10 e 261238

(3) http://www.researchgate.n...

(4) Bell DS. Intravenous Fluid as a Treatment for ME/CFS http://www.davidsbell.com...
(5) Autonomic Nervous System and Chronic Fatigue Syndrome (CFS&ANS) http://clinicaltrials.gov...

(6) Chalder T, Berelowitz G, Hirsch S, Pawlikowska T, Wallace P, Wessely S, Wright D: Development of a fatigue scale.
J Psychosom Res 1993, 37:147-153.

(7) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6. <http://www.biomedcentral....>

(8) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. 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 Mar 5;377(9768):823-36. Epub 2011 Feb 18.

(9) 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.

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

(11) A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. De Becker P, McGregor N, De Meirleir K. J Intern Med. 2001 Sep;250(3):234-40.

It is curious that Dr. van der Meer and colleagues overlooked one of the major cautions regarding the use of Rituximab in ME/CFS.

Although XMRV has proven not to be a pathogen in either CFS or prostate cancer, it hasn’t changed most virologists minds that ME/CFS is an infectious disease with viral involvement. [1, 2] And rituximab is known to activate viruses in patients. This suggests caution must be used in determining which subsets of patients might benefit from this treatment.

Dr. van der Meer and colleagues also attempt to connect this clinical trial, which is supported by other studies, with the purported off label use of antiretrovirals in CFS. However they offer no hard numbers to back up their claim that "many" patients choose to try antiretrovirals. An estimated 17 million patients worldwide have this neuroimmune disease - how many is many?

As well, the authors of the fifth reference given not only do not give a number, they specifically refer to investigators and clinicians who recommend patients not take antiretrovirals at this time.

Like the use of graded exercise in patients with pathological post exertional malaise caution should be used in trying any treatment with the potential for substantial side effects. But, in the end it is up to the patient, and their clinicians, to determine the safest and most effective course of treatment for the individual.

As in any other disease, particularly when effective treatment options are limited, severely ill patients are more inclined to take risks. The answer isn’t to suppress biomedical research, but rather to do more biomedical research making sure not to mix people who do not have a disease with patients who do - a problem specifically noted by Fluge et al in this study. [3]

1] Shin CH, Bateman L, Schlaberg R, Bunker AM, Leonard CJ, et al. (2011) Absence of XMRV retrovirus and other murine leukemia virus-related viruses in patients with chronic fatigue syndrome. J Virol 85(14): 7195–202

2] Dockser Marcus, A. (2011, September 15). Applying Venture Philanthropy to Chronic Fatigue Syndrome. The Wall Street Journal.

3] Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Naess H Dahl O, Nyland H, Mella O, benefit from B-lymphocyte depletion using the anti-CD20 antibody Rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PloS One 6:10 e 261238

It is not so hard to understand why van der Meer and colleagues might be 'astonished' at the use of Rituximab for the treatment of ME/CFS (1), as it admittedly is a far cry from his own stated preference of attempting to 'cure' ME/CFS patients by having them ‘stop labelling themselves as CFS patients' (2). However for the estimated 17 million patients worldwide who actually have the debilitating neuroimmune disease ME/CFS, ie not those in which ‘everyday bodily signs and symptoms are… interpreted as indicating CFS’ (2), high-quality biomedical research and treatment studies are urgently needed. Dr’s Fluge, Mella and co-authors have done a great service to these patients by conducting such a study.

1. Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, et al. (2011) Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS ONE 6(10): e26358. doi:10.1371/journal.pone.0026358

2. Judith B Prins, Gijs Bleijenberg, Jos WM van der Meer Chronic fatigue syndrome and myalgic encephalomyelitis
The Lancet, Volume 359, Issue 9318, Page 1699, 11 May 2002 doi:10.1016/S0140-6736(02)08577-X
http://www.thelancet.com/...(02)08577-X/fulltext

To the editor,

We are glad to address the critics of van der Meer and co-authors as response to our recent paper in PLoS One [1], where we presented a small randomized, double-blind, placebo-controlled study of the CD20-directed antibody Rituximab as intervention in chronic fatigue syndrome (CFS/ME) patients fulfilling the Fukuda criteria.
At one point we totally agree with the critics: Rituximab should not be used to treat CFS/ME outside of clinical studies at present. We also agree that more research is needed.

van der Meer and coauthors have problems believing our results in part based on what they see as atypical response kinetics for Rituximab and a lack of theoretical understanding of why the drug should show efficacy in CFS/ME. We do not support their statement that a response within the first days to weeks necessarily is the usual pattern in other diseases where Rituximab intervention is used. Autoimmune cytopenias and some autoimmune diseases such as acute demyelinating polyneuropathy [2] may respond early, while in other diseases the responses usually start to occur after months. In accordance, the endpoints for clinical studies, or clinical benefit demonstrated in observational studies, are often defined at 6 - 12 months after treatment, with the clinical effects subsiding over the following months or year, such as in rheumatoid arthritis [3], lupus nephritis [4], and primary antiphospholipid antibody syndrome [5]. As an example, in a case study of pulmonary alveolar proteinosis, in which autoantibodies to GM-CSF have been demonstrated, the levels of autoantibodies declined the first three months after Rituximab treatment, while effect on alveolar-arterial gradient was seen at six months, and improvements in pulmonary function tests and CT scans were evident at nine months [6].

The full consequences of the action of Rituximab in other autoimmune diseases are only partly known, and also which of the known modes of action that are of greatest relative importance in individual patients [7]. CFS/ME is not a disease with evident widespread inflammatory lesions as in some established autoimmune conditions and the mode of action could thus be different from that seen in for example rheumatoid arthritis or lupus. Reduction of autoantibody levels (wash-out by reduced production following B-cell depletion) to a critical level before clinical responses become evident could therefore be one plausible mechanism explaining what we observed.

van der Meer and colleagues raise methodological concerns regarding the measurements of fatigue in our study. We used a visual analogue scale for self-reported symptoms every second week during 12 months follow-up. A similar scale was used in a previous study of intervention in CFS/ME [8]. We have not validated the symptom scales used further. However, as it was a randomized study, all patients (Rituximab and Placebo) had the same follow-up. The Fatigue-score was used as the main criterion for response assessment, and the GLM analysis for repeated measures showed a significant interaction time by intervention group, which we believe is the most important result in the study. The data in this analysis are a direct reflection of the self-reported symptom scores registered every second week, where the patients wrote down a number representative of the whole preceding two-week period, thus taking into account the day to day variations in symptoms typical for many CFS/ME patients. The critics question if a physician-rated fatigue score in a subjective complaint is relevant. The reason for including this in the protocol was to see if there was a good agreement between what the patients told us at the consultations and the figures they reported in their files. In general, the patient and doctor values were in good accordance (Figure 2, panels B and D).

van der Meer and colleagues argue that the clinical size of effect seems small. Figure 2 (panel A) shows the self-reported Fatigue-score for each patient, demonstrating the distribution of responders and non-responders at the different time intervals. In panel B, the mean values for Fatigue score in each group are shown and include the counts of the non-responders, also reflecting that the time frames for clinical responses vary among the patients, thus tending to reduce the numerical value at a given time. We do not agree that the clinical effects are small or clinically irrelevant, and as stated in the manuscript the patients assessed these to be important for their quality of life, generally affecting all CFS/ME related symptoms.

Some limitations of our study pointed at by the critics have already been addressed in the paper. The choice of the primary endpoint at three months (based on responses of the first two pilot patients given Rituximab) [9] and the lack of predetermined exact description of responses with respect to duration and extent of improvement, are caused by limited experience with the kinetics of responses after B-cell depletion in CFS/ME. After seeing the first two pilot patients with response on all CFS/ME symptoms, later followed by relapses, and seemingly as the result of the intervention, we made a decision to do a limited randomized study. A phase II study without a control group in a disease with subjective endpoints would probably have problems convincing both study readers and ourselves. Our study size was a balance between having a fair chance of detecting a difference between the intervention groups and what could be handled within a clinical university department, without any industrial or other external economical support for the clinical part of the study.

Concerning the blinding, randomization was done by the hospital pharmacy and the infusion bags packed in a manner that did not disclose their content for either the patients or the nurses administering the infusions. Any complaints during infusions were to be dealt with by the doctors on call and not the researchers. The observed side effects (Table 5) did not clearly indicate to patients or physicians which treatment had been given. We did not (as suggested by the critics) ask the patients which drug they thought they had been given. We believe the blinding for both patient and researchers was good.

van der Meer et al. comment on the high rate of other autoimmune diseases in the patients and their relatives in this series. This is not an original observation and has been noted also by others. One of the senior authors of our manuscript, prof. H. Nyland, is the single physician in Norway who has seen and systematically registered most CFS/ME patients and he confirms this finding his patients. We can agree that including a single case of carpal tunnel syndrome (CTS) as an autoimmune entity is questionable. Nevertheless, the CTS is greatly overrepresented in patients with known autoimmune disease, like diabetes type I, lupus, and rheumatoid arthritis, and is quite often a heralding condition before the systemic autoimmune disease is evident. Although multifactorial aetiology of CTS is a favoured view, a genetic and autoimmune component is probable in many patients. Concerning the question of a relation between a family history of autoimmune diseases and response, the material is of course too small to answer that. Table 1 shows that previous autoimmune disease in patients or first degree relatives is not higher in the Rituximab than in the placebo group.

Importantly, we have not demonstrated that CFS/ME is an autoimmune disease with disease-specific autoantibodies, but we have stated as a hypothesis that the observed clinical pattern of responses and relapses could be compatible with such a mechanism. Alternatively, influence on other aspects of B-cell function could be the key to understand the effects of B-cell depletion in CFS/ME, such as antigen-presentation to T-cells, influence on other immune cells such as dendritic cells, or changes in Th1 and Th2 balance.

Finally, van der Meer and colleagues raise major concern on the fact that we are performing an open-label phase II study, exploring Rituximab induction followed by Rituximab maintenance, instead of a new high-quality randomized study. They also suggest that we overestimate the effects and downplay the possible serious side effects. The critics may have fallen into the same ditch of prejudice as they indicate we have.
We admit the strong and repeated responses to new Rituximab infusion seen in our three pilot patients may have influenced us. We have later treated another lymphoma patient with preexisting CFS/ME who also experienced a clear response on all CFS/ME symptoms from four months after start of treatment (8 cytotoxic chemotherapy courses (CHOP) with addition of Rituximab), and she still has response of CFS/ME symptoms 2 ½ years later. Other physicians treating patients having both CFS/ME and lymphoma elsewhere in the world have informed us of similar responses to Rituximab. The total experience with Rituximab in our opinion warrants a study to optimize the use of the drug.
Based on the current study, there is now a Norwegian national initiative to do a randomized, blinded, multicenter Phase III study to verify or reject the conclusions of the PLoS One study. In the planning of this national study, results of our exploratory phase II study with Rituximab induction and maintenance will be important for the scheduling of the drug administration.

CFS/ME according to Fukuda or Canadian criteria is in many patients a very serious and debilitating disease. Current treatment is for many patients highly unsatisfactory and we believe it is justified to find new interventions and learn more of the pathophysiology, of which we at the time being know little. The side effects of Rituximab in this particular patient group of patients is of course presently largely unknown, although there is vast experience with the drug in B-cell lymphomas and established autoimmune diseases. We believe the severity of disease in many CFS/ME patients balances the known risks. That was also the opinion of most patients who were given the option to participate in the current study at a time when only three pilot patients had been treated with the drug.


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 6:10 e 261238
2. Motoyama R, Yamakawa K, Suzuki S, Kusunoki S, Tanaka M (2011) Rapid improvement by rituximab treatment in a case of demyelinating polyneuropathy with anti-myelin-associated glycoprotein antibody. Rinsho Shinkeigaku 51: 761-764.
3. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, et al. (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350: 2572-2581.
4. Diaz-Lagares C, Croca S, Sangle S, Vital EM, Catapano F, et al. (2011) Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: Pooled data from European cohorts. Autoimmun Rev. epub ahead of print
5. Elazary AS, Klahr PP, Hershko AY, Dranitzki Z, Rubinow A, et al. (2011) Rituximab induces resolution of recurrent diffuse alveolar haemorrhage in a patient with primary antiphospholipid antibody syndrome. Lupus. epub ahead of print
6. Borie R, Debray MP, Laine C, Aubier M, Crestani B (2009) Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J 33: 1503-1506.
7. Kessel A, Rosner I, Toubi E (2008) Rituximab: beyond simple B cell depletion. Clin Rev Allergy Immunol 34: 74-79.
8. Blacker CV, Greenwood DT, Wesnes KA, Wilson R, Woodward C, et al. (2004) Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial. JAMA 292: 1195-1204.
9. Fluge O, Mella O (2009) Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol 9: 28.


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

Most of the issues raised by Van der Meer and colleagues have been kindly addressed by Prof Jonathan Edwards and Prof Olav Mella.

There is however one thing I would like to add.

Van der Meer and colleagues start off by saying that "The finding of Fluge et al [1] that B lymphocyte depletion the anti-CD20 monoclonal antibody, Rituximab (RTX) has beneficial effects in patients with chronic fatigue syndrome is astonishing, particularly since they do not present any theoretical justification for using RTX."

As we all know, many discoveries in medicine are actually made by accident. We are treating one problem, and by accident, find out that the treatment works for something else. A famous example is the discovery that Viagra didn't work very well for hypertension but works really well for erectile dysfunction. As Prof Mella has described, they were treating a patient with lymphoma with Rituximab and then discovered that it works very well for chronic fatigue syndrome or Myalgic Encephalomyelitis as well. With these sort of accidental findings, the theoretical justification can only be sought afterwards obviously.

People who are familiar with ME or CFS as some want to call it, know that there are almost 5000 research papers showing all sorts of physical abnormalities in this very disabling disease. Most of these abnormalities centre around the mitochondria, immune dysfunction and ongoing viral infections.

A recent study by Yabusaki and colleagues from the University of Hawaii showed that 95% of ME/CFS Patients have Anticardiolipin Antibodies, suggesting that ME/CFS may be an autoimmune condition. And they continued by giving the following theoretical justification for using Rituximab in ME/CFS:

"As a possible autoimmune disease, CFS patients may be treated by suppression of the ACA or by diminishing the antigen CL in serum. Previous studies have shown that treatment with monoclonal antibodies to B cells reduces ACA levels to normal in patients with autoimmune disease, leading to clinical improvements.

Specifically, Rituximab, a chimeric monoclonal CD20 antibody, has been shown to normalize high ACA serum titers of patients with autoimmune systemic lupus erythematosus, rheumatoid arthritis, autoimmune thrombocytopenia, and autoimmune hemolytic anemia.
Rituximab may serve as an effective therapeutic agent for ameliorating the symptoms of CFS." (1).

References:
(1) Y. Hokama, C. Empey Campora, C. Hara, T. Kuribayashi,
D. Le Huynh, and K. Yabusaki, Anticardiolipin Antibodies in the Sera of Patients with Diagnosed
Chronic Fatigue Syndrome, Journal of Clinical Laboratory Analysis 23 : 210–212 (2009)

Van der Meer et al. exhort their colleagues, and members of the public, to learn.

As a member of that public, I should like to comment.

The survival of all organisms clearly depends upon learning processes.

However, people with "CFS", who will have specialised in some way, may inadvertently be compelled to learn from those who specialise in other domains.

They must therefore be able to trust certain other people, about whom they may know very little.

"CFS" is a disease area wherein lies an avoidable extra layer of suffering and hardship, much of it the consequence of poor and sometimes misleading information.

Both correspondents Miller and Angus were involved in a clinical trial registered as a RCT (http://www.controlled-tri...), coordinated at Barts and the London.


In their Specialist Medical Care Manual, available at www.pacetrial.org, it is stated that "If participants are insistent that there is an ongoing 'physical' problem, it is rarely helpful to directly challenge them on this point".

As a member of the public mentioned, I was astonished by the lack of any clarification on this issue. Indeed, failing to make their position clear runs counter to their exhortation.

Perhaps in the future we may learn that Fluge and Mella (and team) have become the Norwegian Warren and Marshall.

I concur with the concerns raised by Dr Van der Meer et al. about the measures of disability used to show improvement in this study. Thanks in part to Dr Van der Meer's own work, we now better understand the problems that can be caused by relying upon questionnaire scores as a measure of disability. His study in to the efficacy of CBT as a treatment for CFS showed positive results when published in 2001 and led to much excitement [1]. Sadly, the objective measures of activity levels and neuropsychological performance which were taken before and after treatment as part of his 2001 study, and showed CBT to be of no benefit to patients, weren’t published until 2007 and 2010 [2,3].

If Fluge et al. have the results from objective measures of disability which show Rituximab to be of no benefit to CFS patients, then I would implore them to release this data now, rather than leaving it unpublished for a further decade.

I also agree with Dr Van der Meer’s concerns about the difficulty and importance of successfully blinding this experiment. If patients were aware that they were receiving a treatment expected to bring substantial benefits to them, then questionnaire scores would be expected to rise regardless of the efficacy of treatment or the real impact upon disability levels. If those providing the treatment were also attempting to influence their patient’s cognitions and beliefs about their illness and their role as a patient [4] then results from subjective questionnaire scores are likely to be particularly unreliable. Hopefully the efforts made by Fluge et al. to prevent such distortions should mean that their results are of greater value than many past attempts to study proposed treatments for CFS.

While I share Dr Van der Meer’s preference of a plausible mechanism to be proposed for the use of Rituximab, this preference needs to be understood in the context of two decades of CFS research where all manner of implausible mechanisms have been proposed and imposed upon patients even in light of clear evidence against them, most prominently the fear avoidance and deconditioning theories of CFS [5,6,7]

Many of the points raised by Dr Van der Meer are of merit, and I hope that his concerns are taken seriously by all researchers trying to find meaningful treatments for CFS from now on.

Competing interests declared: None.

[1] Prins JB, Bleijenberg G, Bazelmans E, Elving LD, de Boo TM, Severens JL, van der Wilt GJ, Spinhoven P, van der Meer JW. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet. 2001 Mar 17;357(9259):841-7.

[2] Knoop H, Prins JB, Stulemeijer M, van der Meer JWM, and Bleijenberg G. The effect of cognitive behaviour therapy for chronic fatigue syndrome on self‐reported cognitive impairments and neuropsychological test performance. J Neurol Neurosurg Psychiatry. 2007 April; 78(4): 434–436.

[3] Bleijenberg G, Prins JB, Wiborg JF, Knoop H, Stulemeijer M,. '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.

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