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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

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.
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pone-0026358-g004: 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.

Mentions: Results from immunophenotyping with B-cell counts, for patients in the Rituximab group (responders and non-responders) and the Placebo group, from baseline and at all visits at 1, 2, 3, 4, 6, 8, 10, and 12 months, are shown in Figure 4. At baseline, three out of 30 patients had a B-cell count below the normal range (110–449×106/L). All patients in the Rituximab group were B-cell depleted at one month after the intervention, except for one patient in which B-cells were not adequately depleted until four months after intervention (Figure 4). During follow-up, there were no differences in B-cell levels between patients in the Rituximab group achieving a response (n = 10), and those with no significant response (n = 5) (Figure 4). Many patients treated with Rituximab were not completely B-cell depleted, with values in the range 0–4 (×106/L) (Figure 4). After two infusions of Rituximab two weeks apart, the B-cell levels started to increase from 4–8 months after intervention, and four out of 15 patients had regained B-cell counts in the normal range at the end of follow-up at 12 months. We also performed Taqman qPCR for the B-cell specific CD19 molecule, normalised according to β-actin mRNA, at baseline and during follow-up at 4, 6 and 8 months. These data confirmed the B-cell depletion in Rituximab-treated patients but could not separate the Rituximab responders and non-responders (data not shown).


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026358-g004: 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.
Mentions: Results from immunophenotyping with B-cell counts, for patients in the Rituximab group (responders and non-responders) and the Placebo group, from baseline and at all visits at 1, 2, 3, 4, 6, 8, 10, and 12 months, are shown in Figure 4. At baseline, three out of 30 patients had a B-cell count below the normal range (110–449×106/L). All patients in the Rituximab group were B-cell depleted at one month after the intervention, except for one patient in which B-cells were not adequately depleted until four months after intervention (Figure 4). During follow-up, there were no differences in B-cell levels between patients in the Rituximab group achieving a response (n = 10), and those with no significant response (n = 5) (Figure 4). Many patients treated with Rituximab were not completely B-cell depleted, with values in the range 0–4 (×106/L) (Figure 4). After two infusions of Rituximab two weeks apart, the B-cell levels started to increase from 4–8 months after intervention, and four out of 15 patients had regained B-cell counts in the normal range at the end of follow-up at 12 months. We also performed Taqman qPCR for the B-cell specific CD19 molecule, normalised according to β-actin mRNA, at baseline and during follow-up at 4, 6 and 8 months. These data confirmed the B-cell depletion in Rituximab-treated patients but could not separate the Rituximab responders and non-responders (data not shown).

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