Rituximab binding to CD20. The CD20 proteins are sticking out of the cell membrane, and rituximab, the Y-shaped antibody, is binding to the CD20 proteins (diagram: National Cancer Institute).

In 2011, a scientific report by Øystein Fluge and Olav Mella of the Haukeland University Hospital in Bergen suggested that the symptoms of ME/CFS could be improved with rituximab treatment (Fluge et al, PLoS ONE 2011). The results made a big splash in the ME world, and received widespread coverage in the press and social media (read our essay). Rituximab is a monoclonal antibody against the CD20 protein on the surface of B-lymphocytes, a type of white blood cell. The drug wipes out these B-cells, and has been used to treat diseases (such as some cancers and autoimmune disorders) in which these cells are malignant, overactive or too numerous.

The 2011 results showed ‘lasting improvements in self-reported fatigue’ in 67% of ME/CFS patients on rituximab compared with 13% of patients on placebo during a follow-up phase lasting 12 months. Also, rituximab was also associated with significant improvements in some quality of life measurements, and no serious adverse events were reported. The Norwegian researchers described their results as preliminary and indicating only a “proof of principle”, but were nevertheless intrigued by them and went on to plan further experiments.

Drs Fluge and Mella have just published their next report, this time a phase II study with a single group of 29 ME/CFS patients with illness levels ranging from mild to severe. Each patient was given rituximab (500 mg/m2; two infusions two weeks apart), followed by ‘maintenance’ rituximab infusions after 3, 6, 10 and 15 months, with follow-up for 36 months. The idea was to explore the effect of rituximab over a longer period, the type and durations of responses to treatment, and any adverse effects. The trial also gave patients in the placebo group in 2011 the chance to have rituximab treatment.

Overall, major or moderate responses to rituximab – defined as lasting improvements in self-reported fatigue score – occurred in 18 of the 28 patients receiving rituximab induction and maintenance treatment (an overall response rate of 64%, similar to that observed in 2011). There was a lag time in responses to treatment, and responses lasted for 105 weeks in the 14 ‘major responders’ and 69 weeks in four ‘moderate responders’. Importantly, the patients who responded to treatment also had significant improvements in quality of life, whereas non-responders did not. Responders also reported substantial improvements in their ME/CFS symptoms. Six of the nine patients who were in the placebo group in the 2011 study had a clinical response within 12 months of the rituximab maintenance infusions. At end of 36 months, some of the patients responding to treatment were still in ongoing clinical remission. As Dr Fluge says, “Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years…Suddenly, their limbs started to work again and their hands were no longer cold or sweaty.”

The fact that sustained clinical responses occurred in around two-thirds of ME/CFS patients undergoing prolonged B-cell depletion with rituximab maintenance infusions is a very promising result. The Norwegian researchers point out that lag times and patterns of responses to rituximab seen in this study accord with response patterns to rituximab in some established autoimmune diseases. They suggest that autoimmune disease, involving B-lymphocytes and elimination of long-lived autoantibodies, may underlie ME/CFS in a subgroup of patients. It could be, as Dr Fluge notes, that an infection can trigger the body to produce antibodies that then turn against a person’s own tissues, possibly affecting the circulation. It may be significant that 12 patients in the study (41%) had first-degree relatives with an autoimmune disease (including rheumatoid arthritis, Sjøgren’s syndrome, ulcerative colitis and thyroiditis), though whether a genetic predisposition is involved in ME/CFS patients generally remains to be determined. Rituximab was found to be relatively safe overall, although two patients had an allergic reaction to the drug and two had an episode of uncomplicated late-onset neutropenia.

The next phase of Drs Fluge and Mella work on rituximab in ME/CFS has been launched – a randomized, double-blind, placebo-controlled phase III study of 152 patients from five centres in Norway (four in university hospitals), who are being followed up for 24 months. The authors are also conducting a smaller study on patients with severe or very severe ME/CFS, using the same rituximab treatment protocol. As the authors “do not encourage the use of rituximab for ME/CFS outside of approved clinical trials”, and as no equivalent treatment trials are ongoing anywhere else, we await their results with great interest.

B-Lymphocyte depletion in myalgic encephalopathy/chronic fatigue syndrome. An open-label phase II study with rituximab maintenance treatment. Fluge Ø, et al. PLoS One, 2015 Jul 1; 10(7): e0129898. Read more (full text).
Antibody wipeout found to relieve chronic fatigue syndrome. New Scientist, 2015 July 1. Read more.
Funding rituximab studies in UK. ME Research UK, 2014. Read more.
Norwegian Rituximab Studies. ME Research UK, 2012. Read more.
Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. Fluge Ø, et al. PLoS One, 2011; 6(10): e26358. Read more (full text).