by Oystein Fluge, Ingrid G. Rekeland, Katarina Lien, Hanne Thurmer, Petter C. Borchgrevink, Christoph Schafer, Kari Sorland, Jorg Assmus, Irini Ktoridou-Valen, Ingrid Herder, Merethe E. Gotaas, Oivind Kvammen, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Sissel S. Martinsen, Ann E. Lonar, Ann-Elise H. Solvang, Arne E.S. Gya, Ove Bruland, Kristin Risa, Kine Alme, Olav Dahl, Olav Mella in Annals of Internal Medicine [Preprint April 2, 2019]
Research abstract:
Background:
Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective:
To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS.
Design:
Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942)
Setting:
4 university hospitals and 1 general hospital in Norway.
Patients:
151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years.
Intervention:
Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n =
74).
Measurements:
Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes
from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures.
Results:
Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, −5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, −0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.
Limitation:
Self-reported primary outcome measures and possible recall bias.
Conclusion:
B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.
Comments:
Annals of Internal medicine – summaries for patients: Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
The researchers noticed that a few patients with ME/CFS who later developed cancer had improvement of their ME/CFS symptoms when they received cancer treatments. One of these treatments included rituximab, a drug that is often used to treat inflammatory diseases (for example, rheumatoid arthritis) and lymphoma. They did a few small trials that also suggested that rituximab might be a beneficial treatment of ME/CFS.
Annals of Internal Medicine editorial: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Trial Fails to Confirm Earlier Observations of Rituximab’s Effectiveness, by Peter C. Rowe, MD [Behind paywall]
Kavli Trust: No effect of rituximab treatment in patients with ME/CFS
The researchers comment:
The study provides valuable information on the symptom course of ME/CFS patients during two years close follow-up in a clinical trial. A subgroup of patients experienced symptom improvement during the observation period. It is difficult to say whether this is the natural course of the disease, or whether other mechanisms such as placebo effects due to high expectations, come into play…
Although side effects were reported by patients who received both the study medication and placebo, the participants generally tolerated the medication well. Many symptoms that were reported as possible side effects, could also be interpreted as fluctuations in the ME/CFS symptoms. Among the 15 patients who reported a general worsening of their symptoms over time, more patients had received placebo than rituximab.
EurekAlert: In phase 3 trial, rituximab not associated with clinical
improvement in patients with ME/CFS
The author of an accompanying editorial from Johns Hopkins University School of Medicine [Peter C. Rowe, MD] praises the sound methodology and sophistication of the trial and notes that a substantial challenge in ME/CFS research is the heterogeneity of the illness. For this reason, future research should be stratified by disease duration and may need to exclude or accommodate for specific subgroups, such as those who are unlikely to respond to treatment and those with a current flare during the trial period.
Medpage Today: Rituximab Fails in Chronic Fatigue
Potential explanations for the discrepancy in results in this trial and the earlier studies included high placebo responses, uncertainty over ME/CFS symptom fluctuations over time, and possible patient selection bias.
The lack of significant improvements with B-cell depletion in this study ‘weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunological basis,’ Fluge’s group noted.
‘The profound level of impaired function of affected individuals warrants a new commitment to hypothesis-driven clinical trials that incorporate and expand on the methodological sophistication of the rituximab trial,’ Rowe stated in his editorial.
Limitations of the study, the researchers said, included self-referral and self-reported outcome measures.
Background: Current case definitions for myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) require an individual to report a ‘substantial reduction’ in activity levels, when compared to premorbid functioning. However, little guidance is provided on how to measure these reductions, as well as what level of reduction should be deemed ‘substantial,’ leading to inconsistencies in how this criterion is applied across research settings.
