Rituximab (multiple brands) did not improve symptoms in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), new research finds.
|Note: The ME Association had first reported these disappointing results when they were announced at the end of 2017. Yesterday saw final publication of the phase III clinical trial which also revealed ‘adverse events' following treatment with Rituximab and placebo in people with ME/CFS.|
Results from the 2-year randomized, placebo-controlled, double-blind, multicenter RituxME trial comparing rituximab infusions with placebo in 151 patients with ME/CFS were published online April 1 in Annals of Internal Medicine.
The study was conducted by Øystein Fluge, MD, PhD, of Haukeland University Hospital, Bergen, Norway, and colleagues.
ME/CFS is characterized by debilitating fatigue, postexertional malaise, sleep disturbance, cognitive dysfunction, and pain, among other symptoms.
Believed to affect about one million people in the United States, it is associated with extremely reduced quality of life.
“Rational treatments are urgently needed,” Fluge and colleagues write.
The B-cell-depleting monoclonal antibody rituximab is approved for use in adults with several types of cancers and autoimmune conditions, including non-Hodgkin lymphoma and chronic lymphcytic leukemia, and as second-line therapy for rheumatoid arthritis.
The rationale for testing rituximab in ME/CFS came from several previous findings. Initially, Fluge and coauthor Olav Mella, MD, PhD, both oncologists, had anecdotally observed improvement in long-standing ME/CFS symptoms in patients treated with rituximab for cancer.
A subsequent randomized, placebo-controlled, 12-week phase 2 trial that included 30 patients showed benefit in several secondary endpoints after two rituximab infusions given 2 weeks apart.
|“We hypothesized that ME/CFS in a subgroup of patients could involve a variant of an autoimmune disease mechanism with a role for B lymphocytes,” Fluge and colleagues write.|
They also cite a significantly increased risk for B-cell lymphoma among elderly patients with ME/CFS.
|“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,” they say.|
In an accompanying editorial, Peter C. Rowe, MD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, notes,
|“It is difficult to reconcile the phase 3 trial results with the earlier observations of clinical improvement. The earlier study participants may have differed from those in the phase 3 trial with regard to the presence of autoantibodies or other biological factors that influenced response rates to rituximab.”|
Rowe writes that the heterogeneity of the illness adds to the challenge of researching treatments for it. The current study used one of the more restrictive case definitions of ME/CFS, the Canadian Consensus Criteria.
Rowe notes, “Persons with ME/CFS often meet criteria for several comorbid conditions, each of which could flare during a trial, possibly obscuring a true beneficial effect of an intervention.”
No Differences With Rituximab, Placebo in Clinical Endpoints
The study was conducted at four university hospitals and one general hospital in Norway and included 151 patients. All patients in the trial met the Canadian Consensus Criteria for ME/CFS and had had the condition for 2 to 15 years.
The rituximab intervention involved two infusions 2 weeks apart at doses of 500 mg/m2 of body surface area, followed by maintenance infusions of 500 mg at 3, 6, 9, and 12 months, or similar infusions of placebo.
One of two primary outcomes, repeated measures of fatigue scores, which assessed fatigue, postexertional exhaustion, need for rest, and daily functioning on the basis of self-report over 24 months, did not differ significantly between the treatment groups during follow-up (P = .80). The difference in average fatigue score between the patients who received placebo and those who received rituximab was an insignificant 0.02 points.
Similarly, the overall rate of response, defined as a fatigue score of at least 4.5 on a 0 – 6 scale, in which higher numbers indicated improvement, for at least 8 consecutive weeks was 35.1% with placebo and 26.0% with rituximab, which was not a significant difference (P = .22).
There were also no differences in secondary outcomes, including responses to the Short Form–36 Health Survey (P = .67) or measures of function and fatigue severity.
|Adverse events considered to be related to the intervention occurred in 33.8% of the rituximab group and 16.3% of the placebo group. In the rituximab group, 31 serious adverse events occurred in 20 patients (26.0%); all 20 patients required hospitalization. In the placebo group, 16 serious adverse events occurred in 14 patients (18.9%). In that group, there was one unintended pregnancy, and 15 patients were admitted to hospital.|
Results Point to Need for Examining ME/CFS Subgroups
Fluge and colleagues say that the negative outcome of this trial “should spur research to assess patient subgroups and further elucidate disease mechanisms, of which recently disclosed impairment of energy metabolism may be important.”
Rowe says that although this study does weaken the case for rituximab, “other immunologic abnormalities in ME/CFS deserve further investigation,” including the overlap of symptoms with mast cell activation syndrome.
Rowe also suggests that future research could include an open treatment run-in period, which might allow better control of comorbid conditions. Another approach that he suggests would be to provide treatment to all patients initially, and then randomly assign only those who responded to treatment to either continue or discontinue treatment.
He notes that enrolling only patients with a specific biomarker might help match disease subgroup to the intervention. Rowe concludes by saying,
|“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.”|
- Medscape Medical News: Rituximab Fails to Improve Symptoms in ME/CFS (by Miriam E. Tucker, 02 April 2019)
- Patient Summary by trial authors: Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Annals of Internal Medicine, 02 April 2019)
- Editorial by Dr Peter Rowe: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Trial Fails to Confirm Earlier Observations of Rituximab's Effectiveness (Annals of Internal Medicine, 02 April 2019)
- Full paper: B-Lymphocyte Depletion in Patients With ME/CFS: A Randomized, Double-Blind, Placebo-Controlled Trial (Annals of Internal Medicine, 02 April 2019)
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. In addition, Haukeland University Hospital has patents and patent applications related to B-cell depletion therapy for ME/CFS. Fluge is an inventor in these applications. Rowe is co–primary investigator on the data management and coordinating center for the NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Collaborative Research Centers and is a member of the Scientific Advisory Board of Solve ME/CFS.
Image credits: Drs. Fluge and Mella (Tor Erik H.Mathiesen), Dr Peter Rowe (Solve ME/CFS Initiative).