Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study

Abstract

Background: Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

Methods and findings: In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.

Conclusion: The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.

Trial registration: ClinicalTrials.gov NCT00848692.

Conflict of interest statement

Competing Interests: 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. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Study flow-diagram.

Approximately 60 patients with CFS diagnosed by a neurologist were identified from the hospital files and contacted by telephone for an interview, and 36 of these were invited for a further thorough assessment. During 12 months follow-up, one out of 15 patients in the placebo group was excluded from further analysis after 28 weeks due to pregnancy, and one after 42 weeks due to study withdrawal and patient's decision to start alternative therapy.

Figure 2. Fatigue scores in Rituximab and Placebo groups, self-reported and physician-assessed.

In panel A, the self-reported Fatigue scores were calculated for each patient every second week, from the mean of the four symptoms: Fatigue, Post-exertional exhaustion, Need for rest, Daily functioning. Then the mean values in Fatigue scores for the time intervals during follow-up were plotted. In panel C, the physician-assessed Fatigue scores were calculated from the mean of the same four symptoms, registered by the physician at the visits in the outpatient clinic. In panel B and D, estimated marginal means for self-reported and physician-assessed Fatigue scores during follow-up are shown. The scales on Y-axes were 0–6 (0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement). The differences in distribution of Fatigue scores during follow-up, between the Rituximab and Placebo groups, were assessed by General Linear Model (GLM) for repeated measures, analysing the effects of time, the interaction time by intervention group, and the overall difference between intervention groups. Below panels C and D, the estimates for differences in mean Fatigue scores between the Rituximab and Placebo groups at the specific time intervals during follow-up, with 95% CI and p-values from the GLM (tests of within-subjects contrasts) are presented. In addition, Holm-Bonferroni step-down adjusted p-values for these time intervals are shown (five comparisons).

Figure 3. CFS symptom changes during follow-up for patients in the Rituximab group with significant responses.

In panels A–J, changes in Fatigue score (black), Cognitive score (red), Pain score (green), “Other symptoms” score (orange), and “CFS overall” score (blue), during 12 months follow-up are shown for the 10 patients in the Rituximab group with significant improvement. The scales on Y-axes were 0–6 (0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement). Also shown are the B-cell numbers from immunophenotyping of peripheral blood mononuclear cells during follow-up (×106/L).

Figure 4. B-lymphocytes during follow-up.

B-cell numbers from immunophenotyping of peripheral blood during follow-up are shown, for patients in the Placebo group (black, n = 15), patients in the Rituximab group with significant response (red, n = 10), and patients in the Rituximab group with no response (blue, n = 5). The B-cell value zero was substituted by 0.1 (to be able to plot on the log scale). B-lymphocyte counts ×106/L (normal range 110–449). The error bars denote mean ± SEM.