Norwegian Rituximab Studies

The publication of a scientific report in October 2011 showing an improvement of symptoms with rituximab (Fluge et al, PLoS ONE 2011) made a big splash in the ME world, and received widespread coverage in the press. Rituximab is a monoclonal antibody against the CD20 protein mainly found on the surface of a type of white blood cell, B-lymphocytes. The drug eliminates these B-cells, and has therefore been used to treat diseases (such as some cancers and autoimmune disorders) in which these cells are malignant, overactive or too numerous.

There is an interesting background to this investigation. Originally, the researchers at Haukeland University Hospital, Bergen noticed that one patient with ME/CFS experienced “unexpected and marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin’s disease”. Because of this, they conducted a pilot case series in 2009 to explore the clinical effects of rituximab in 3 more people with ME/CFS, and found a “significant clinical response”. Building on these intriguing results, the researchers planned their newly published investigation – a double-blind, placebo-controlled phase II study – using 30 ME/CFS patients randomised to receive either rituximab or saline (two infusions two weeks apart) with follow-up for a whole 12 months.

The predefined “primary end-point” – self-reported fatigue score 3 months after treatment – was negative (i.e. there was no significant difference between rituximab and placebo). As the authors point out, however, differences in fatigue between the two groups were actually most evident after 6–10 months, suggesting that 3 months was too short a time to evaluate the effects of rituximab on symptoms, something that subsequent investigations will take into account. So, over the whole follow-up, a major or moderate “overall response” (defined as lasting improvements in self-reported fatigue) was seen in 67% of patients on rituximab compared with 13% of patients on placebo (p=0.003; see Table). Furthermore, rituximab was also associated with significant improvements in some quality of life measurements, and, what’s more, no serious adverse events were reported in patients receiving rituximab.

The Norwegian researchers suggest that the “delayed” responses to rituximab (starting after 2–7 months), in spite of rapid B-cell depletion, support the idea of ME/CFS as an autoimmune disease in which the gradual elimination of autoantibodies from the body leads to symptom improvement. However, they describe their results as preliminary and indicating only a “proof of principle”. In fact, they were probably as surprised as anyone else by the spin given by the media to these tentative findings. The next phase of the work is at the planning stage – a Norwegian national initiative to undertake a randomized, blinded, multicenter Phase III study to verify or reject these findings. Given the drastic action of rituximab (the destruction of B-cells which have an important role in immunity), and the cost of the drug (several thousand pounds for a single course), it is most likely that other research groups will proceed cautiously, awaiting the Phase III trial results with interest.

This essay originally appeared in Breakthrough, Spring 2012.