Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.
The risk for a first relapse was six times higher in patients receiving interferon β or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.
The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet in Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”
He presented the findings on October 13 at ECTRIMS 2021.
Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.
They identified all patients who initiated an injectable therapy (interferon β or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between January 1, 2011, and December 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if he or she stopped receiving therapy.
The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
Rituximab Reduced Relapses
The researchers included 1938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.
Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.
For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio (HR) for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.
In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.
But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.
The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.
Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
“The Uncertainty Continues”
“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Alping added.
Dr Robert Fox
Although rituximab is not indicated for MS, many clinics are using it in this population, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio, told Medscape Medical News. Fox was not involved in the study.
“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”
The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Fox.
The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Fox observed.
Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”
But the disability findings may be the most important part of the study, according to Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.
“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”
The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Alping has disclosed no relevant financial relationships. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.
37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2021. Presented October 13, 2021.
Follow Erik Greb on Twitter: @MedscapeErik.