Long-term rituximab lowers NMOSD relapse risk, eases disability

Study participants received lower doses than usually given

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Treatment with rituximab significantly reduces the risk of relapse and lessens disability in neuromyelitis optica spectrum disorder (NMOSD) patients with antibodies against aquaporin-4 (AQP4), according to a long-term, retrospective Australian study.

Most of the analyzed patients received an initial infusion of rituximab at 1,000 mg, given as two separate 500 mg infusions two weeks apart, followed by single 500 mg doses, which is “lower than the doses most commonly reported in the literature,” the researchers wrote.

The findings support the efficacy of rituximab in NMOSD, but also highlight the need for further studies to determine the treatment’s optimal dosing in this patient population, the researchers noted.

The study, “Long-term efficacy and safety of rituximab in the treatment of neuromyelitis Optica Spectrum disorder,” was published in the Multiple Sclerosis Journal – Experimental, Translational and Clinical.

NMOSD occurs when the immune system mistakenly attacks healthy cells of the central nervous system, which consists of the brain and spinal cord. This leads to damaging inflammation in the spinal cord and optic nerves, which relay signals between the eyes and the brain. Left untreated, the inflammation can make symptoms suddenly worsen, or relapse. Each relapse causes new damage that accumulates over time, sometimes leading to paralysis and vision loss.

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Most NMOSD cases are associated with self-reactive antibodies against AQP4, a protein found at the surface of neuron-supporting cells.

Rituximab (sold as Rituxan, among others) is an antibody-based therapy developed for certain blood cancers that works by promoting the death of antibody-producing immune B-cells. Given as an into-the-vein, or intravenous, infusion, it is commonly used off label in NMOSD. Data from small studies have supported its ability to prevent relapses, even in racially diverse populations, and ease disability in NMOSD.

However, data from large, controlled clinical trials are lacking, and the optimal dosing of rituximab in NMOSD remains unclear.

Initially, rituximab regimens for NMOSD were based on the doses used for blood cancers, usually an initial dose of 1,000 mg infused twice, two weeks apart, followed by 1,000 mg maintenance doses. But an increasing number of studies have reported rituximab’s efficacy in NMOSD with lower doses.

To evaluate rituximab’s long-term safety and efficacy in NMOSD, a team of researchers retrospectively analyzed pharmacy dispensing and clinical records of NMOSD patients treated with rituximab at two major hospitals in Brisbane, Australia, from January 2005 to July 2021.

The analysis covered 37 patients, 86% of them women, with a mean age of 42 at rituximab start. Most (73%) were positive for anti-AQP4 antibodies, while the remaining 10 patients were AQP4-negative.

Rituximab was the first disease-modifying therapy for most patients. The most common treatment regimen was an initial 1,000 mg dose, given as two 500 mg infusions two weeks apart, followed by single doses at 500 mg.

AQP4-positive patients were followed for a median of about 4.5 years, and those without such antibodies for a little over three years. During follow-up, 23 patients (62%) required routine redosing of rituximab. AQP4-positive patients received a median of 10 rituximab infusions, and AQP4-negative patients a median of six.

Following rituximab treatment, 12 AQP4-positive patients (44%) experienced a total of 15 relapses, and four AQP4-negative patients (40%) experienced a total of 11 relapses. Most relapses occurred after six months of starting the treatment, and within six months of the last rituximab dose.

In both groups, 27% of the relapses were reported along with B-cell reconstitution, at a median of about nine months after the last rituximab dose.

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Milder relapses

Also in both groups, 69% of relapses after rituximab were mild, compared with 18% before treatment. No patient experienced a severe relapse after rituximab, whereas 16% had experienced them before treatment.

Among AQP4-positive patients, the annualized relapse rate (ARR), a measure of the number of relapses adjusted to a one-year time window, dropped significantly after rituximab treatment, from 0.38 to 0.1.

While the AQP4-negative group also experienced a reduction in the ARR with rituximab, the difference was not statistically significant.

Rituximab was also associated with significantly less disability, as shown by a drop in the median Modified Rankin Scores (mRS) scores from 2 to 1 at last follow-up. The mRS assesses a person’s disability, with higher scores indicating worse disability.

The most commonly reported adverse events were infections (32%), which were most commonly mild in severity. There was one fatal case of a generalized blood infection that started in the urinary tract and one case of severe COVID-19-associated pneumonia in one unvaccinated patient.

Four patients (11%) had to discontinue rituximab due to adverse events. That included two patients who experienced allergic reactions.

“Our study provides long-term evidence that rituximab may be an efficacious therapy for NMOSD and carries a favorable safety profile, at lower doses than have been traditionally used,” the researchers wrote. “The optimal dosing of rituximab for the treatment of NMOSD warrants further investigation, ideally with [an appropriately controlled trial] comparing different doses of rituximab for efficacy and safety,” they concluded.