Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. — CFSMEATLAS
Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Rekeland, Ingrid G, Sørland, Kari, Neteland, Lisbeth Lykke et al. · PloS one · 2024 · DOI
Quick Summary
This study followed patients with ME/CFS for six years after they received either rituximab (an antibody treatment), cyclophosphamide (a chemotherapy drug), or placebo in two earlier clinical trials. The researchers tracked how much the patients could do in their daily lives using standard questionnaires. Cyclophosphamide showed the most improvement, with 44% of those patients reaching good functional levels after six years, but the rituximab and placebo groups showed smaller benefits.
Why It Matters
This is among the longest follow-up studies of immunomodulatory treatment in ME/CFS, providing evidence that cyclophosphamide may produce sustained functional improvements in a subset of patients. These findings support the hypothesis that an autoimmune mechanism underlies ME/CFS in some patients and justify continued research into safer, targeted immune therapies rather than dismissing immunological approaches.
Observed Findings
Cyclophosphamide recipients showed sustained improvement over six years (SF-36 PF increased from 35.4 to 56.7), with 44.1% reaching SF-36 PF ≥70 and 17.6% reaching normal range (≥90).
Rituximab showed modest improvement (SF-36 PF: 32.9→42.4→45.5) with only 27.6% reaching SF-36 PF ≥70 at six years.
Placebo group showed similar improvement to rituximab (SF-36 PF: 32.3→45.5→43.1), with only 20.4% reaching SF-36 PF ≥70.
Worsening at six years was least common in the cyclophosphamide group (5.9%) compared to rituximab (10.3%) and placebo (14.8%).
No serious unexpected adverse reactions were reported across the six-year follow-up period.
Inferred Conclusions
Cyclophosphamide may modulate disease course beneficially in a ME/CFS subgroup, with improvements sustained over six years.
These results support the hypothesis that autoimmune mechanisms contribute to ME/CFS in at least some patients, justifying continued mechanistic research.
The data suggest need for targeted, less toxic immune-modulatory treatments rather than chemotherapy-level interventions.
Both rituximab and placebo produced similar outcomes, questioning the specificity of B-cell depletion for ME/CFS as currently applied.
Remaining Questions
What This Study Does Not Prove
This study does not prove cyclophosphamide should be used outside research settings—the authors explicitly caution against this due to toxicity risks. It does not establish which patients will benefit from these treatments or why some improve while others do not. The open-label design of the cyclophosphamide trial means placebo effects and observation bias cannot be entirely excluded.
Tags
Symptom:Fatigue
Method Flag:PEM Not DefinedWeak Case DefinitionMixed Cohort
What baseline clinical, immunological, or molecular characteristics predict which patients will respond to cyclophosphamide or rituximab?
Why did the open-label cyclophosphamide group show substantially better outcomes than the double-blind rituximab arm—is this a true treatment difference, placebo effect, patient selection, or study design artifact?
What are the optimal dosing regimens and treatment combinations for safer immune-modulatory approaches in ME/CFS?
Does sustained improvement after six years continue further, or do patients experience late relapses beyond this timeframe?