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Treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with rituximab (Rituxan, MabThera) did not lead to clinical improvement in a randomized, multicenter trial.

Over 2 years of follow-up, the difference in fatigue scores between patients who had received rituximab and those given placebo was only 0.02 (95% CI -0.27 to 0.31, P=0.80), according to Øystein Fluge, MD, PhD, of Haukeland University Hospital in Bergen, Norway, and colleagues.

In addition, an overall response was seen in 26% (95% CI 17.5 to 36.7) of the rituximab group but in 35.1% (95% CI 25.2-46.5) of the placebo group, the researchers reported in .

"This carefully designed trial did not identify statistically significant differences between groups on any primary or secondary measure," observed Peter C. Rowe, MD, of Johns Hopkins University School of Medicine in Baltimore, who wrote an . "In fact, the rates of improvement in the two groups were almost identical."

The cause of ME/CFS remains unknown, but the disorder is characterized by profoundly reduced quality of life resulting from fatigue, postexertional malaise, disturbances of sleep, and cognitive problems. Hypersensitivity also is common, and may relate to autonomic or immune dysfunction.

"The socioeconomic costs are high, and elucidation of disease mechanisms, improvement in diagnostic approaches, and rational treatment are urgently needed," Fluge and colleagues stated.

The rationale for conducting a phase III trial of rituximab in ME/CFS originated in these authors' observation that several patients with a long history of this disorder who subsequently developed cancer reported alleviation of their ME/CFS symptoms after chemotherapy and B-cell depletion with rituximab.

The researchers then conducted a small of 30 patients who received two infusions of rituximab or placebo, and secondary endpoints favored rituximab. This was followed by that included 29 patients who received six infusions during 15 months and were followed for 3 years. Half of those patients reported clinical improvements in physical function, which the authors suggested might reflect beneficial effects of B-cell depletion on ME/CFS.

"We hypothesized that ME/CFS in a subgroup of patients could be caused by immunologic dysfunction with a role for B lymphocytes," they wrote.

Accordingly, they enrolled 151 patients, more than 80% of whom were women, from five Norwegian centers. Patients' mean age was 37 and disease duration averaged 8 years.

Overall fatigue scores were calculated from mean scores of 0 to 6 for fatigue, postexertional exhaustion, need for rest, and daily functioning. Overall response was defined as a score of 4.5 or higher for 8 consecutive weeks.

Treatment consisted of induction with two infusions at a 2-week interval of rituximab, 500 mg/m² of body surface area, or placebo, which was followed by maintenance infusions at months 3, 6, 9, and 12.

In the five individual centers, the rates of response to rituximab ranged from 17.6% to 37.5%, while rates of response among placebo recipients ranged from 25% to 54.5%.

For secondary endpoints, there also were no significant differences in average scores between the rituximab and placebo groups, with these between-group differences:

• Short Form 36 (SF-36) physical function, -0.41 (95% CI -7.73 to 6.92, P=0.67)

• Function level, -0.21% (95% CI -4.18 to 3.76, P=0.48)

• SF-36 physical component score, -0.44 (95% CI -2.90 to 2.02, P=0.63)

• Fatigue Severity Scale, -0.25 (95% CI -2.44 to 1.95, P=0.61)

In general, patients in both treatment groups reported "slight but significant improvements" for these self-reported outcomes during the 2-year follow-up. Adverse events were reported in 81.8% of patients receiving rituximab and 64.9% of those given placebo. There were 31 serious adverse events in 20 patients receiving rituximab and 16 serious adverse events in 14 patients receiving placebo.

Adverse events that were considered possibly or probably related to the treatment intervention totaled 33.8% in the rituximab group and 16.2% in the placebo group. "The relatively large number of unrelated adverse events probably reflects the low tolerance for physical and cognitive strain in patients with ME/CFS," the authors wrote.

Potential explanations for the discrepancy in results in this trial and the earlier studies included high placebo responses, uncertainty over ME/CFS symptom fluctuations over time, and possible patient selection bias.

The lack of significant improvements with B-cell depletion in this study "weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunological basis," Fluge's group noted.

"The profound level of impaired function of affected individuals warrants a new commitment to hypothesis-driven clinical trials that incorporate and expand on the methodological sophistication of the rituximab trial," Rowe stated in his editorial.

Limitations of the study, the researchers said, included self-referral and self-reported outcome measures.