Objective:

To review the evolving clinical trials investigating novel therapeutic strategies in autoimmune encephalitis with a focus on targeted and biological therapies.

Background:

Autoimmune encephalitis encompasses a heterogeneous group of antibody-mediated disorders affecting the central nervous system. Although corticosteroids, IVIG, plasma exchange, and B-cell–targeting monoclonal antibodies are the mainstay of AE treatment, a subset of patients are refractory to treatment or have a relapse. Novel biological and cellular therapies that modulate cytokine signaling, complement activation, and autoreactive lymphocyte survival are currently being explored.

Design/Methods:

We conducted a literature search of 45 ongoing and completed trials, case reports and cohort studies evaluating IL-6 inhibitors (tocilizumab, satralizumab), FcRn antagonists (efgartigimod, rozanolixizumab), complement inhibitors (eculizumab), and advanced therapies such as bortezomib, telitacicept, and CAR-T cell therapy.

Results:

Recent multicenter Phase 3 studies such as the CIELO trial (satralizumab in NMDAR- and LGI1-IgG–positive AE) are evaluating IL-6 blockade as an adjunct or alternative to conventional therapy. FcRn antagonists (efgartigimod, rozanolixizumab) aim to reduce pathogenic IgG levels by inhibiting antibody recycling. Bortezomib, telitacicept and CAR-T cell therapy are being explored in the preclinical and early clinical stages for refractory AE.

Conclusions:

Next-generation therapies targeting IL-6, FcRn, and complement pathways, along with plasma cell directed and cellular therapies, are emerging therapies in AE management. Early data suggest favorable tolerability and immunologic response, though larger controlled studies are needed to define efficacy, safety, and optimal patient selection.