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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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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.
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pone-0026358-g001: 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.

Mentions: Most of the participants were recruited from patients referred to Department of Neurology, Haukeland University Hospital, which is a tertiary referral centre. After examining the patient hospital files from approximately 60 patients, 36 patients who after a telephone interview still seemed to fulfil the inclusion criteria were invited to a new thorough assessment at the Department of Oncology, Haukeland University Hospital (ØF and OM). Six out of these 36 patients chose not to participate (Figure 1).


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026358-g001: 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.
Mentions: Most of the participants were recruited from patients referred to Department of Neurology, Haukeland University Hospital, which is a tertiary referral centre. After examining the patient hospital files from approximately 60 patients, 36 patients who after a telephone interview still seemed to fulfil the inclusion criteria were invited to a new thorough assessment at the Department of Oncology, Haukeland University Hospital (ØF and OM). Six out of these 36 patients chose not to participate (Figure 1).

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