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

Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O - PLoS ONE (2011)

Bottom Line: There were no serious adverse events.Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. oystein.fluge@gmail.com

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.

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Related in: MedlinePlus

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).
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pone-0026358-g002: 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).

Mentions: The effect of intervention was assessed by studying the interaction effect between time and intervention group, from GLM for repeated measures of self-reported Fatigue score. There was a significant interaction time by intervention group in favour of the Rituximab group (p = 0.018), and an overall difference between groups (p = 0.045) (Figure 2, panels A and B, Table S2). Similarly, in GLM for repeated measures of physician-assessed Fatigue score, the interaction time by intervention group (p = 0.024) and the overall difference between groups (p = 0.021) were both significant in favour of the Rituximab group (Figure 2, panels C and D, Table S2).


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

Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O - PLoS ONE (2011)

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).
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Related In: Results  -  Collection

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pone-0026358-g002: 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).
Mentions: The effect of intervention was assessed by studying the interaction effect between time and intervention group, from GLM for repeated measures of self-reported Fatigue score. There was a significant interaction time by intervention group in favour of the Rituximab group (p = 0.018), and an overall difference between groups (p = 0.045) (Figure 2, panels A and B, Table S2). Similarly, in GLM for repeated measures of physician-assessed Fatigue score, the interaction time by intervention group (p = 0.024) and the overall difference between groups (p = 0.021) were both significant in favour of the Rituximab group (Figure 2, panels C and D, Table S2).

Bottom Line: There were no serious adverse events.Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. oystein.fluge@gmail.com

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.

Show MeSH
Related in: MedlinePlus