Off-label rituximab (Rituxan) showed superior drug survival rates and better clinical efficacy as first-line treatment in relapsing-remitting multiple sclerosis (RRMS) compared with other common therapies, the latest in a series of a Swedish registry studies found.

Significantly more newly-diagnosed RRMS patients remained on rituximab each year than injectable interferon or glatiramer acetate (Copaxone), dimethyl fumarate (Tecfidera), fingolimod (Gilenya), or natalizumab (Tysabri), Fredrik Piehl, MD, PhD, of the Karolinska Institute in Stockholm, and colleagues reported online in JAMA Neurology.

Rituximab showed significantly fewer clinical relapses and less neuroradiologic disease activity than injectable drugs or dimethyl fumarate and borderline significance over fingolimod and natalizumab.

And in a Swedish county where rituximab was the main initial treatment for RRMS, patients demonstrated better outcomes than those who lived where other first-line disease-modifying treatments (DMTs) predominantly were used, the researchers noted.

“Collectively, our findings suggest that rituximab performs better than other commonly used disease-modifying treatments in patients with newly diagnosed RRMS,” they wrote.

Rituximab, which is used off-label for MS in the U.S. and other countries, is similar to ocrelizumab (Ocrevus); both target CD20 immune B-cells instead of T-cells. Last year, the FDA approved ocrelizumab for relapsing and primary progressive multiple sclerosis.

“This real-world usage paper represents a somewhat unique natural history experiment in that there are significant regional differences in the use of rituximab and other medicines in similar patients across Sweden,” John Corboy, MD, of the University of Colorado, who was not involved in the study, told MedPage Today.

“It further supports the concept that anti-CD20 molecules are not only more effective than what many consider to be first-line therapies, but, as noted in the clinical trials, they have an adverse event and tolerability profile that is equal to, if not better than, the same first-line therapies,” he added.

The study included 494 individuals in Stockholm and Vasterbotten counties who received a diagnosis of RRMS from Jan. 1, 2012 to Oct. 31, 2015. Patients were observed until April 30, 2016.

The primary outcome was discontinued therapy for any reason, including conversion to secondary progressive MS and pregnancy. Secondary outcomes were relapses, the presence of gadolinium-enhancing (Gd+) lesions on magnetic resonance imaging (MRI) scans, adverse events, and reasons why patients stopped treatment.

The median age of patients was about 34, and 32% were men. Of the total sample, 43.5% received an injectable DMT (interferon or glatiramer acetate), 24.3% received rituximab, 17.4% received dimethyl fumarate, 10.1% received natalizumab, 3.4% received fingolimod, and 1.2% received another initial treatment.

Regional preferences were clear: 42 of 52 patients (81%) in Vasterbotten received rituximab, compared to 78 of 442 (18%) in Stockholm.

Pregnancy (3.3%) was the most common reason why patients stopped rituximab. Breakthrough disease and adverse events were the most frequent reasons why patients stopped other therapies: 38.1% and 27.9% for injectable DMTs, 16.3% and 14.0% for dimethyl fumarate, and 23.5% and17.6% for fingolimod, respectively.

Patients treated with rituximab demonstrated fewer clinical relapses and less neuroradiologic disease activity than patients who received injectable DMTs or dimethyl fumarate. Rituximab also showed numerically lower relapse rates and Gd+ lesions than fingolimod and natalizumab, but those findings did not reach statistical significance.

“In conjunction with data from this and other research groups, this is a cogent argument that anti-CD20 DMTs should be strongly considered as not only appropriate for those with more severe disease or those switching off other highly effective therapies, but also should be considered — indeed, suggested — as first-line for the average newly diagnosed MS patient, without the interference of ‘step editing’ mandated by so many insurance companies,” Corboy noted.

Most arguments for starting with less effective DMTs center around safety and price, Piehl and colleagues noted. Newer, more effective agents have been associated with risks like progressive multifocal leukoencephalopathy and often command a much higher price.

“It is undisputed that the safety record of first-line injectable DMTs in use since more than two decades is superior to that of newer DMTs, which is of high relevance in particular for the risk-benefit assessment of long-term treatment in patients with mild to moderate disease,” they wrote. Rituximab’s off-label status remains a barrier, too, subjecting it to varying insurance regulations.

This study is limited by its nonrandomized design and small sample sizes for some treatment groups, the authors cautioned. While data supported that patients switched drugs for efficacy reasons, there may be other reasons, including geographic differences in logging adverse events.

Follow-up guidelines also differed among drugs, they noted. Until 2014, two yearly visits were recommended for rituximab, natalizumab, and fingolimod, and one annual visit was recommended for injectable DMTs. This may have affected how adverse events were recorded. Since 2015, follow-up guidelines have been identical.

The limited study period reduced the ability to analyze long-term disability outcomes, the authors added. Lack of volumetric MRI data also prohibited differences in atrophy rates from being detected.