B-cell depletion achieved with rituximab infusions may not be associated with clinical improvement in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), according to a study published in the Annals of Internal Medicine.
The investigators had previously examined the effects of rituximab-mediated B-cell depletion and immunomodulation therapies in individuals with ME/CFS, and results from the study indicated an improvement that may be related to the intervention. They hypothesized that B lymphocyte-driven immunologic dysfunction may underlie ME/CFS pathology in certain patients and sought to further evaluate this possibility in the current trial.
This RituxME study was a multicenter phase 3 parallel-group randomized double-blind placebo-controlled trial (Clinicaltrials.gov identifier: NCT02229942) designed to investigate the relationship between B-cell depletion in ME/CFS and clinical responses. A total of 151 participants age 18 to 65 years with ME/CFS for 2 to 15 years were enrolled between September 2014 and September 2015. Individuals were randomly assigned to receive rituximab (n=77; mean age, 37.8 years; 83.1% women; mean disease duration, 8.4 years) or placebo (n=74; mean age, 35.5 years; 81.1% women; mean disease duration, 7.6 years). Rituximab treatment consisted of 2 infusions 2 weeks apart of 500 mg/m2 of body surface area (induction) followed by 4 infusions (maintenance infusions; 500 mg fixed dose) at 3, 6, 9, and 12 months.
Patients were seen at 3-month intervals and followed for 24 months. The study’s primary outcome was the overall response rate (ie, a fatigue score ≥4.5 for ≥8 weeks consecutively) fatigue scores evaluation over the 24-month study period. Secondary outcomes included Short Form-36 (SF-36) Health Survey and Fatigue Severity Scale scores and self-reported functioning over 24 months, as well as assessments of changes at 18 months vs baseline of the same measures and physical activity.
The response rates were 26.0% and 35.1% in patients treated with rituximab and placebo, respectively (difference, 9.2%; 95% CI, −5.5% to 23.3%; P =.22). Across 24 months, there were no significant differences between groups in terms of fatigue score (mean score difference, 0.02; 95% CI, −0.27 to 0.31; P =.80) or any of the secondary outcomes.
A total of 63 (81.8%) and 48 (64.9%) participants experienced adverse events in the rituximab and placebo groups, respectively. Serious AEs were reported by 20 (26.0%) and 14 patients (18.9%) treated with rituximab and placebo, respectively.
Study limitations include possible recall bias secondary to self-reporting and potential unintended heterogeneity in the sample.
“The lack of clinical effect of B-cell depletion in this trial weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunologic basis,” noted the authors, who recommended that future research explore patient subgroups and seek to elucidate pathophysiologic mechanisms.
An accompanying commentary echoed the clinical trial investigators’ findings, pointing out that the current results were at odds with prior findings, weakening the case for rituximab treatment in this population, but not eliminating the possibility of an immunologic basis for ME/CFS.
The RituxME trial received funding from the Norwegian Research Council, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, and the legacy of Torstein Hereid. The research group for ME/CFS at Haukeland University Hospital receives funding from the Kavli Trust.
Please see original article for conflict of interest disclosures.
Fluge Ø, Rekeland IG, Lien K, et al. B-lymphocyte depletion in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Ann Intern Med. April 2019:1-9. doi:10.7326/m18-1451