Concerns about rituximab study, letters to PloSOne, 27 October 2011

October 28, 2011


Original paper in PLoSOne, 27 October 2011.

Rituximab in CFS; more research needed

To the Editor,

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 beyond a very small case series. It is not so much the finding that a form of immunotherapy may work, but rather the peculiar late response (between 6 – 10 months). Such a late response has not been seen in other conditions in which RTX works. The authors had not expected this either, as they did not include a clinical response at this late stage in the primary endpoints.

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)?

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.

What also remains unclear is whether the categorical definition of improvement was determined before the analysis; the discussion suggests this was done post hoc, suggesting this needs replication before any reliable interpretation is possible. Whether a physician-rated fatigue score is a relevant measure for a subjective complaint like fatigue is another questionable issue.

Although there seems to be a statistically significant group by time effect on self-rated fatigue change by linear regression modelling, the clinical size of effect seems small; the best change score approaches 4 at 32 weeks, consistent with “slight improvement”.

Further to the immunological aspects of the treatment, the proportion of patients with either a history or a family history positive for autoimmune disease is high. Did this subgroup show a better response to RTX than the others? The list of autoimmune conditions is rather wide and (perplexingly) includes carpal tunnel syndrome. It would be useful to see how these were balanced across groups.

RTX has beneficial effects not just on auto-antibody-mediated disease: in many instances B cell depletion probably acts by interfering with auto-antigen presentation or by decreasing the T helper 17 response [2, 3]. So if the effect of RTX is real, the finding may guide us to understanding the pathophysiology of CFS, however, in all other autoimmune diseases where RTX therapy is effective, the benefit is observed in days to weeks, consistent with the mechanism of action. The authors present no convincing statement as to a biologically plausible mechanism that may be effected by their intervention. The delayed effect observed is not consistent with the effect of RTX in other autoimmune diseases, a delayed response in ITP for example is seen within 8 weeks [6].

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.

Jos WM van der Meer (Radboud University Medical Centre Nijmegen, the Netherlands),
Andrew Lloyd (University of New South Wales, Sydney, Australia),
Matthew Buckland (Barts and the London NHS Trust, London ,UK),
Alistair Miller (Royal Liverpool University Hospital, Liverpool UK),
Dedra Buchwald (University of Washington, Seattle, WA, USA),
Brian Angus (John Radcliffe Hospital, Oxford, UK).

References:
1] 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
2] Yanaba K, Bouaziz JD, Matsushita T, Magro CM, St Clair EW, Tedder TF. B-lymphocyte contributions to human autoimmune disease. Immunol Rev. 2008 Jun;223:284-99
3] van de Veerdonk FL, Lauwerys B, Marijnissen RJ, Timmermans K, Di Padova F, Koenders MI, Gutierrez-Roelens I, Durez P, Netea MG, van der Meer JWM, van den Berg WB, Joosten LA. The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum. 2011;63:1507-16.
4] van Kuppeveld FJ, van der Meer JWM. XMRV and CFS-the sad end of a story. Lancet. 2011 Jun 20. [Epub ahead of print]
5] Cohen J, Enserink M. Virology. False positive. Science. 2011;333:1694-701
6] Brændstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB, Andersen I, Schmidt K, Andersen TA, Peterslund NA, Birgens HS, Plesner T, Pedersen BB, and Hasselbalch HC. Rituximab Chimeric Anti-CD20 Monoclonal Antibody Treatment for Adult Refractory Idiopathic Thrombocytopenic Purpura. American Journal of Hematology 78:275–280 (2005)
No competing interests declared.


Other replies to the Norwegian paper can be viewed HERE.

They include letters from: Professor Jonathan Edwards, Emeritus Professor, Department of Medicine, University College London; and Tom Kindlon, information officer for The Irish ME/CFS Association.

11 thoughts on “Concerns about rituximab study, letters to PloSOne, 27 October 2011”

  1. As far as I can tell from their websites, these are all proper doctors. I suspect that what they are really suggesting is that even if the Haukeland University Hospital have serendipitously found an active agent effective against CFS, they should nevertheless hand over the research initiative to better qualified people (themselves) since they don’t believe these people are sufficiently clued up.

  2. Interesting that this questionable comment is published here, yet none of the responses have made it to the MEA. Hmm.

    To see all the comments to the Rituximab article, see here: http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c&root=info%3Adoi%2F10.1371%2Fannotation%2F43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c

    Here is my comment:

    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

    (Tony, I’m trying HTML markup for the first time here. As there is no preview or edit facility, if it doesn’t work, would you be kind enough to sort it out for me? Thanks, xjx)

    1. Hi Jace

      No problems with the HTML mark-up this end.

      I’ll be adding the extra letters by Professor Jonathan Edwards and Tom Kindlon to the story sometime over the weekend – and any others that have emerged since I last looked.

      Tony

  3. The only surprise is how long it’s taken for disparaging remarks about Prof Mella and Dr Fluge to appear.

    A successful treatment for M.E? Dear, dear, that can’t be allowed – even though most, if not all of the concerns (above) were addressed in the original paper. Wouldn’t it be appalling if we could be treated without a psycholgist/iatrist in sight.

    I can almost hear empires crumbling.

    Tusen takk, Prof Mella and Dr Fluge og lykke til!

  4. I am too unwell to process all the information in this post and the subsequent comments, but I sincerely hope that the Norwegian doctors make sure their research is above criticism if we are not to have our hopes raised and dashed once more as happened with the XMRV research.

    1. The viruses found in Lombardi et al. are not VP62/XMRV. Consequently all the negative papers using VP62/XMRV are invalidated. There is no study that refutes the findings, as not one looked for HGRVs. Lo et al. did however confirm ME patients are infected with human gammaretroviruses.

  5. I don’t think any Science is above criticism. The will to criticise is enough. Epistemology is a Philosophical wing that can be applied to Science which allows us to deny all knowledge of certainty. Epistemology channelled by a consensus of authority figures, while fallacious, has enough efficacy to dislodge respect from inconvenient Science. Access to the press not only enables such criticism, but also amplifies it. This gives those with money and power a much clearer channel with which to service their own confirmation bias.

    The reason people are so disappointed by XMRV is because it has been over-simplified and turned into a false dichotomy. If you read the press over the last few years, the critiques come from the same Scientists over and over, and when you analyse the language used, it stinks of politics.

    Anyone who questions what is going on is accused of being a conspiracy theorist, and then they conflate the very idea of having an intellectual opposition to these people with ‘death threats’ yet fail to confirm a single conviction along with the evidence to prove that such a person was genuinely an ME patient or advocate. On the strength of this information, someone looking to discredit vocal opposition could simply send themselves an anonymous threatening email.

    Conversely, I’d challenge any ME patient to go to the press and say anonymous Scientists have been threatening them. I’m guessing they wont print it without confirming the source.

    That, is the power the line here.

    Perhaps as they inevitably take the Scimitar out of the Scabbard and start working over the Rituximab story, more people will awaken to the reality of our situation.

    The biological nature of ME does damage to a lot careers and published research. It also kills finance for a lot of people who have been misappropriating it from the MRC for nonsense.

    For those really looking to support Rituximab I think we need another paper that would pre-empt the larger scale trial. It’s time we had a paper that looked at the most compelling biomarkers found in ME patients and graded them all for cost and accuracy.

    I think it’s something all ME advocacy groups could agree on. We need to get away from subjective self report results and start to compel researchers to include more objective markers. I believe that with these objective markers, even if Rituximab doesn’t pan out as a panacea, it could be the straw that broke the psychological camel’s back.

  6. One of the authors was the Co-Leader of the PACE Trial centre at the John Radcliffe Hospital, Oxford.

  7. Yes, we shouldn’t expect any remission whilst on Rituximab, if this were genuine psychological disorder, or a relapse when the treatment is stopped. However, there is the issue of studies using criteria that are inappropriate and do not provide a differential diagnosis. If that continues, results will not be confirmed.

    At least with this area the researchers will have to use the drug, and won’t be able to claim they have validated assays, whilst actually using a none existent synthetic retrovirus that has no relationship to HGRVs.

  8. 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
    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.

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