Research Underscores Rituximab's Utility in Treating MS

Rituximab is frequently used off-label as a treatment for relapsing-remitting multiple sclerosis (MS) because it induces the depletion of circulating B-cell and T-cell lymphocytes and targets CD20 protein in B cells that are responsible for the production of antibodies.

A French study¹ recently presented at the European Committee for Treatment and Research in Multiple Sclerosis investigated the impact of rituximab on regulatory T-cells (Treg), which play a role in immune modulation and have been identified as promoting oligodendrocyte differentiation and remyelination.

A total of 43 patients with MS, 19 with relapsing-remitting and 24 with progressive disease, received 1000 mg rituximab intravenously, followed by a maintenance dose of 1000 mg in 6 months.

Researchers recorded circulating lymphocyte kinetics (B CD19/B CD20/B CD27/T CD4/T CD8/Treg/NK cells) before the first infusion (M0) and 6 months later (M6). Secondary outcomes were the annualized relapse rate (ARR), expanded disability status scale (EDSS), and MRI activity.

Mean (SD) EDSS at baseline was 5.2 (1.4) and 5.3 (1.5) at 6 months, respectively. ARR significantly decreased at M6 from a mean 1.18 (1.2) to 0.18 (0.6) (P=.00094). MRI activity was reported in 11% of patients, compared with 56% at baseline. Levels of CD19+ and CD27+ memory B-cell lymphocytes were significantly depleted at M6 (both P <.0001). Although percentages of CD8+ lymphocytes remained unchanged, a significant increase in CD4+ lymphocyte levels was found at M6 [M0: 44.7% (10.8) to M6: 52.6% (8.8); P=.0008].

Among CD4+ T cells, activated Treg percentage remained unchanged. However, quiescent Treg significantly increased (M0: 1.56% [1.36] to M6: 2.3% [2.2]; P=.036). There was no observed change in natural killer and natural killer T-cell populations.

These results suggest that rituximab treatment is associated with an unexpected upregulation of circulating CD4+ lymphocytes and quiescent Treg levels, the latter of which the researchers hypothesize could reflect the reduced conversion of Treg into activated Treg in rituximab responders. However, future trials with a larger cohort and a longer follow-up are needed.

A second study² presented at the same meeting compared rituximab with fingolimod, dimethyl fumarate, and natalizumab in patients with MS. Most had relapsing-remitting disease. Researchers found the odds of discontinuing treatment at 24 months or less was lower for patients taking rituximab versus fingolimod and dimethyl fumarate. The researchers said that rituximab demonstrated the lowest unadjusted disease activity outcomes of all the treatments, which are considered highly effective therapies.

The study included 182, 271, 342, and 451 patients who initiated rituximab, fingolimod, dimethyl fumarate, and natalizumab, respectively, between January 2010 and October 2013. The primary outcome was the probability of drug discontinuation by the end of year 2. The researchers controlled for age, disease duration, type of MS, gender, and enhancing lesion at baseline.

At 24 months, 46 (25.3%), 93 (34.3%), 161 (47.1%), and 147 (32.6%) patients discontinued rituximab, fingolimod, dimethyl fumarate, and natalizumab, respectively. Fingolimod versus rituximab had an adjusted odds ratio (aOR) of 1.96 (95% CI, 1.23-3.13; P=.005) of discontinuation by 24 months. Dimethyl fumarate versus rituximab had an aOR of 3.32 (95% CI, 2.15-5.13; P <.001). Natalizumab versus rituximab had an aOR of 1.50 (95% CI, 0.99-2.28; P =.109).

The leading cause of discontinuation of rituximab and natalizumab were issues involving insurance (9.9%), and being positive for John Cunningham Virus (12.6%), respectively.

Adverse events were the leading cause for discontinuation of fingolimod (17%) and dimethyl fumarate (24.0%). Fewer rituximab-treated patients (14.8%) experienced disease activity during follow-up compared with fingolimod (34.7%, P <.001), dimethyl fumarate (33.6%, P <.001), and natalizumab (22.2%, P =.037).

References

1. Maillart E, Ungureanu A, Derai D, et al. Impact of rituximab on Treg lymphocytes in MS patients. Presented at the European Committee for the Treatment and Research in Multiple Sclerosis annual meeting, October 10-12, 2018; Berlin, Germany. Abstract P554. https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/228398/elisabeth.maillart.impact.of.rituximab.on.treg.lymphocytes.in.ms.patients.html?f=media=3*search=rituximab*browseby=8.

2. Vollmer B, Nair K, Sillau S, Corboy J, Vollmer T, Alvarez E. Comparison of rituximab vs fingolimod, dimethyl fumarate and natalizumab in the treatment of multiple sclerosis: two year experience. Presented at the European Committee for the Treatment and Research in Multiple Sclerosis annual meeting, October 10-12, 2018; Berlin, Germany. Abstract P562. https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/228406/brandi.vollmer.comparison.of.rituximab.vs.fingolimod.dimethyl.fumarate.and.html?f=menu=14*media=3*speaker=546718*browseby=8.