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

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