Efficacy and Safety of Ofatumumab Treatment for Anti‐NMDA Receptor Autoimmune Encephalitis (OFF‐AE): A Prospective, Multicenter Cohort Study

Objective Ofatumumab presents a potentially promising alternative to current second‐line immunotherapy for refractory anti‐N‐methyl‐D‐aspartate receptor autoimmune encephalitis (NMDAR‐AE). We aimed to evaluate the efficacy and safety of ofatumumab as a novel second‐line immunotherapy for NMDAR‐AE. Methods This prospective, multicenter, nested cohort study compared patients with NMDAR‐AE from the CHina Autoimmune encephalitiS outcomE study registry (CHASE) recruited between October 2011 and February 2024, treated with and without ofatumumab. The primary outcome was the proportion reaching a favorable functional outcome (modified Rankin Scale [mRS] score ≤2) at the last follow‐up. Secondary outcomes included mRS scores and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores over the first 24‐month follow‐up and the proportion with further mRS score improvement after ofatumumab initiation. A propensity score matching was performed to balance major confounders. Results A total of 715 patients with AE were screened. Fifty‐eight propensity score‐matched patients with NMDAR‐AE each in the ofatumumab group and non‐ofatumumab group were analyzed. Fifty‐four patients (93.1%) in the ofatumumab group achieved further mRS score improvement with a median time of 14 days from ofatumumab initiation, and 53 (91.4%) reached a favorable functional outcome at the last follow‐up. For those who failed first‐line immunotherapy, the ofatumumab group demonstrated a faster mRS score and CASE score improvement and more frequently reached a favorable functional outcome at the last follow‐up compared with the non‐ofatumumab group (87.9% vs. 64.7%, odds ratio [OR] 3.95; 95% confidence interval [CI] 1.12–13.94; p = 0.026). No serious adverse events associated with ofatumumab treatment were reported. Interpretation Ofatumumab showed substantial efficacy and safety, particularly in patients who failed first‐line immunotherapy, warranting its consideration in NMDAR‐AE management. ANN NEUROL 2025;98:80–92