Fluge and Mella respond to van de Meer about rituximab, letter to PlosOne, 31 October 2011

From PlosOne, 31 October, where the full range of letters can be read.

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.

8 thoughts on “Fluge and Mella respond to van de Meer about rituximab, letter to PlosOne, 31 October 2011”

  1. Mella & Fluge have gifted an opportunity for the MEA to expose the hypocrisy of the Psychology fraternity and their delusionary beliefs with regards to ME/cfs.

    Please learn from the example set by a past master of media manipulation (Pof Simon Wessely) and seize the moment to advocate strongly on our behalf, with an orchestrated media campaign to back up the work of these Norwegian researchers.

  2. Yes, well said Dionysus. MEA, AFME etc. please join forces to get behind this research and get it publicised.
    you have previously written to the Science Media Centre about bias; what was the result of that? I dont recall seeing any follow-up, sorry if Ive missed it.
    If this Rituximab work doesn’t get a good airing in the press it will only prove yet again how most of our media is only interested in a sensational story preferably around some group of people they can scapegoat and demonise, and how willing they are to be the mouthpiece of what has to be the most uncaring and reckless British government in recent memory.

  3. MLV retroviruses also cause autoimmune symptoms and infect B cells. Therefore this research supports the HGRVs hypothesis for ME. The authors should also look at the Th17 shift identified in people with ME according to the Canadian criteria and then the Fukuda criteria who are also infected with HGRVs. The delayed response is because the pathology caused by the viruses takes time to subside once the viruses are eliminated. Unfortunately this will not be the entire story for HGRVs, as MLV viruses propagate in other tissues and will not be eradicated. Hence why some patients will not respond and will become sick again.

  4. Dr Charles Shepherd

    The MEA is working very closely with the UK representatives of the Norwegian research group in order to obtain media publicity for the trial results. Examples so far: BBC, New Scientist, Daily Mail……

    I briefed (written and verbal) the All Party Parliamentary Group on ME at Westminster, and the Forward ME Group at the House of Lords, on the results last week.

    I have discussed the results, and a possible preliminary protocol for a UK clinical trial, with leading experts in the use of this drug and with the chair of the MRC Expert Group on ME/CFS research.

    The MEA has made it clear that the Ramsay Research Fund would be very happy to look at funding proposals for a UK clinical trial.

    One note of caution: This is one small phase 2 clinical trial. We need to see the results from further clinical trials before coming to any conclusions about the way in which this drug might work in ME/CFS and whether or not it is an effective form of treatment for what may be a sub-group of people with ME/CFS who have an autoimmune component.

    I am not aware of any scientific support for the view that it is acting against a retroviral infection. The evidence in support of a retroviral link to ME/CFs is now very slim indeed.

    And we do not want to see a repeat of the false hopes XMRV fiasco.

    I will be updating the MEA Questions and Answers on Rituximab tomorrow.

    There is more discussion on the trial on the MEA Facebook page.

    Re SMC: We received a short and very negative response after a long delay and did not therefore pursue this any further.

    1. The support that Rituximab is acting against a MLV-related virus can be seen in this study, Lombardi et al. Lo et al. and 40 years of MLV research. MLVs infect B cells.

      There is no evidence against the HGRVs detected in Lombardi et al. and Lo et al., as all studies that used VP62 to optimise their assays have be invalidated. The viruses found have been proven to not be VP62/XMRV and a synthetic clone is not integrated and these viruses integrate into high CG content, so cannot mimic the conditions needed for PCR.

      So the belief that, ” evidence in support of a retroviral link to ME/CFs is now very slim indeed”, is incorrect. VP62/XMRV assays are indeed a fiasco.

    2. Here are two scientists who say the negative papers are invalidated because they failed to diagnostically validate their assays.

      “In my view the CDC paper should not have been published without a proper positive control, eg patient samples known to contain XMRV. If I had reviewed the CDC paper that’s what I would have asked for.” Professor Racaniello


      “It’s just not sufficient to show that something can detect something in a plasmid template. It’s hard to know if it’s going to detect something in a matrix that’s as complicated as blood or cellular DNA. So I think that’s probably one of the biggest reasons for why people find different results..” Dr Singh


      Singh broke her own golden rule in her own paper Shin et al. Easy enough to have that paper retracted though.

  5. Thankyou for your work Dr Shepherd in trying to get a clinical trial going and for pursuing publicity for the recent Rituximab paper.
    Very sorry to hear of more negativity from Science Media Centre – ironic that they were supposed to have been set up to promote good and rigorous science reporting, yet in their actions regarding ME they do the exact opposite and are surely in the pockets of some pretty hefty vested interests.

  6. I have had in the past same type of response using low/high dose of prednisone or even cortef…There is no doubt in my mind it is swelling inside the body and an over-reactive immune system…This latest medicine study could actually be reducing either c.pneumonaie levels or actually making spinal fluids flow properly by reducing swelling…Here is also a paper that makes a lot of sense and also why medicines from johns hopkins 1995 study did not work on patients. This explains quite a bit of a viable link from a Neuro Surgeons findings… ‘neurally mediated hypotension2005’ where they show possible links to cfs and chiari and/or stenosis…This is why I believe I had always good responses on these steroids above from reducing swelling and it was not from these medicines giving my body more cortisol…I knew of a doctor who completely recovered by taking prednisone but do not know if he stayed well but he did recover at that time…Also I had one of the highest spinal fluid pressures ever recorded at University of Miami and was put on 80 mg. of prednisone and was swimming in the ocean days later and almost felt normal…Even my antibodies levels dropped to normal levels…I feel very strongly that something is definitely going on in the neck/brain area and this swelling/block is making immune system turn on thinking it is fighting an infection or a type of miscommunication between brain and immune system…I also have every symptom of chiari/stenosis list which are just about identical to cfs symptoms…Even my high pressure headaches were result of increased intracranial pressure and prednisone or cortef reduced this pressure and Ithink the pressure of fluid is because something blocked in the neck/brain area…Even my brain spect scan looked normal on steroids…Beta blockers never worked nor did florinef or neurontin…I can recall the doctors words who recovered he thought ‘ A snarled communication between the brain and the immune system’… When i took my mri from Montreal who said it was normal to the University of Miami Neurologist he said my mri was not normal and if I recall his words he said ventricles were abnormal and i think something to do with menninges…Even the Johns Hopkins doctors said tilt table tests returned to normal after surgical procedures on patients and I have read numerous positive full recoveries and also some failures which is common in chiari…This could be why science has not found an infection as any cause or could be infection triggered chiari symptoms or possible dehydration states…

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