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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

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).
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pone-0026358-g003: 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).

Mentions: The self-reported symptoms scores were plotted every second week for each patient. These data are shown for the 10 responders in the Rituximab group (Figure 3, panels A–J), and for the two patients with significant improvement in the Placebo group (Figure S4, panels A–B). These charts show that symptoms in all the four main categories tend to follow each other in time. Also included in these plots are the B-cell numbers during follow-up.


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)

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).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198463&req=5

pone-0026358-g003: 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).
Mentions: The self-reported symptoms scores were plotted every second week for each patient. These data are shown for the 10 responders in the Rituximab group (Figure 3, panels A–J), and for the two patients with significant improvement in the Placebo group (Figure S4, panels A–B). These charts show that symptoms in all the four main categories tend to follow each other in time. Also included in these plots are the B-cell numbers during follow-up.

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