Mycophenolate Mofetil Demonstrates Therapeutic Potential as Adjunctive Treatment for Anti-NMDA Receptor Encephalitis

Recently published findings from the LEARN trial, an open-label, blinded-end point, randomized controlled study, showed that treatment with mycophenolate mofetil (MMF) resulted in reduced risk of relapse among patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). Overall, the therapy was safe over the 24-month treatment period, further emphasizing its potential as a long-term adjunctive treatment to first-line therapy in this patient population.¹

The prospective, randomized, Chinese-based study comprised 100 patients with NMDARE, aged 14 and older, who received first-line treatments within 2 weeks of presenting to the hospital and had a modified Rankin scale (mRS) score of 2 or more. Led by Zhen Hong, Department of Neurology, West China Hospital of Sichuan University, patients were randomized to either first-line treatment with or without MMF (0.5 g, twice per day), with outcomes like relapse rate and time to relapse as the primary end points.

In the study, first-line treatment dosing comprised either intravenous methylprednisolone (IVMP) treatment, intravenous immunoglobulin (IVIg), or plasma exchange (PLEX). For relapse analysis, follow-up was limited to the last visit (≥ 24 months) or relapse date, yielding median follow-ups of 30 months for MMF-treated patients (MMF+) and 36 months for those without (MMF–). Overall, the majority of patients in each group received a combination of IVIg and IVMP with an interval of less than 7 days as the first-line treatment (MMF+: 70.5%; MMF–: 85.7%), while less than 10% of patients used PLEX.

Throughout the study, there were a total of 18 relapse events from 16 patients, most of which were not on MMF treatment. Among those to relapse, 3 were assigned to MMF+ (5.9%) and 13 were not given MMF (26.5%). The lower relapse rate, demonstrated in a Cox proportional hazards model (4.2; 95% CI, 1.5-11.6; P = .006) was further supported by all sensitivity analyses. Notably, patients with onset age less than 30 years, female sex, CASE score greater than 20, and timely first-line treatment or a higher cerebrospinal fluid /serum NMDAR-IgG titer appeared to be more responsive to MMF treatment.

"MMF typically exhibits a delayed onset of action, often requiring weeks to months to achieve significant therapeutic effects," Hong et al wrote. "In contrast, cyclophosphamide can start showing effects within days to weeks due to its potent immunomodulatory action, while rituximab typically induces B-cell depletion within 2–4 weeks after a single intravenous infusion. Thus, for patients with NMDARE with highly active disease or at the acute phase of relapse, rituximab and cyclophosphamide might be more beneficial to rapidly control disease activity. In contrast, MMF’s advantages lie in its ability to maintain long-term disease stability and prevent relapse, making it more suited for maintenance therapy rather than acute intervention."

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Treatment response, considered at least a 1-point improvement in mRS score within 4 weeks of baseline, was more likely in the MMF+ group, with a relative rate ratio of 1.8 (95% CI, 1.1-3.4; P = .03). In the MMF+ group, 5.9% of patients received rescue immunotherapy compared with 26.5% of those in the MMF– group (RR, 0.3; 95% CI, 0.1-0.7; P = .006). Improvements of at least 2 points on mRS were found in 27.4% of those in the MMF+ group vs 22.5% of those in the MMF– cohort (P = 0.8).

Over the 24-month period, patients with NMDARE receiving long-term MMF showed lower disability, fatigue, and depression scores, along with better cognitive performance and a higher seizure freedom rate at 6 months (76.5% vs 53.1%; P = 0.02), despite no significant differences in overall functional outcomes at 12 or 24 months. No added benefit was seen in non-relapsing patients.

"Despite our research showing that MMF maintenance therapy may reduce the relapse rate of NMDARE, the overall relapse rate of NMDARE is significantly lower than that of MS and NMOSD," the study authors noted. "Thus, long-term immunosequential therapy may provide limited benefits for non-relapsing patients, as shown in our subgroup analysis. This underscores the need for further research into the necessity and cost-effectiveness of prolonged therapy. Individualized treatment plans are essential, with MMF being more beneficial for high-risk patients."

In terms of safety, the rates of treatment adverse events (AEs), infections, and serious infections in the MMF+ treatment periods were consistent with those in the MMF– groups during the study periods. Throughout the trial, Serious infection rates remained low over time, with no increases in infections, neutropenia, or tumors, and most MMF-related adverse events were mild or moderate, with no deaths or anaphylaxis reported.

REFERENCE
1. Gong X, Liu Y, Ma Y, et al. Long-term maintenance of mycophenolate mofetil in anti-NMDA receptor encephalitis (LEARN): a multicentre, open-label, blinded-endpoint, randomised controlled trial. Neurol, Neurosurg, & Psych. Published online February 26, 2025. doi: 10.1136/jnnp-2024-335400.