B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.
Fluge, Øystein, Rekeland, Ingrid G, Lien, Katarina et al. · Annals of internal medicine · 2019 · DOI
Quick Summary
Researchers tested whether a drug called rituximab, which reduces B cells (a type of immune cell), could help ME/CFS patients. Over 150 patients received either rituximab infusions or placebo over one year. Unexpectedly, the placebo group actually did slightly better than the treatment group, and neither group showed significant improvement in fatigue or function.
Why It Matters
This large, rigorously designed trial contradicts earlier preliminary findings suggesting B-cell depletion benefits and demonstrates that not all immunological abnormalities in ME/CFS translate to therapeutic targets. The negative result helps redirect research toward other pathophysiological mechanisms and prevents unnecessary exposure to an immunosuppressive therapy with potential serious side effects.
Observed Findings
Overall response rate (fatigue ≥4.5 for ≥8 consecutive weeks): 35.1% in placebo group versus 26.0% in rituximab group (P=0.22, not statistically significant).
Mean fatigue score over 24 months showed no significant difference between groups (difference 0.02; P=0.80).
Secondary outcomes including self-reported function, Fatigue Severity Scale, and SF-36 components showed no significant between-group differences over 24 months.
Serious adverse events occurred in 26.0% of rituximab recipients compared to 18.9% of placebo recipients.
Placebo response rate (35.1%) was unexpectedly high and exceeded the treatment group response rate.
Inferred Conclusions
B-cell depletion via rituximab is not an effective treatment for ME/CFS despite promising phase 2 data, suggesting the immune abnormality observed in ME/CFS may not be therapeutically reversible through this mechanism.
The high placebo response rate indicates substantial symptom variability or placebo effects in ME/CFS trials, complicating treatment evaluation.
Rituximab's adverse event profile and lack of efficacy do not support its use in ME/CFS patient populations.
Remaining Questions
Why did phase 2 trials show promise while this larger phase 3 trial did not—could patient selection, disease duration, or biomarker subgroups explain the discrepancy?
What This Study Does Not Prove
This study does not prove that B cells play no role in ME/CFS pathophysiology—it only shows that depleting B cells with rituximab does not improve clinical outcomes in this population. The findings do not rule out benefit in ME/CFS subgroups (e.g., those with specific biomarkers) or rule out other immune mechanisms. It also does not address whether other B-cell-targeting strategies might be effective.
Does any ME/CFS patient subgroup (defined by immune markers, disease duration, or phenotype) benefit from B-cell depletion, or is the entire approach ineffective?
What alternative immune mechanisms drive ME/CFS if B-cell depletion is ineffective, and how should future immunological research be prioritized?
Why was the placebo response rate so high (35.1%), and does this reflect true variability in ME/CFS or measurement/recall bias?